TK

Human herpesvirus 1 (strain 17) (HHV-1) (Human herpes simplex virus 1)

NA

UL23

Herpesviridae thymidine kinase family

Transferase

ATP binding.Thymidine kinase activity.

Atransferrinemia (ATRAF) [MIM:209300]: A rare autosomal recessive disorder characterized by abnormal synthesis of transferrin leading to iron overload and microcytic hypochromic anemia. {ECO:0000269|PubMed:11110675, ECO:0000269|PubMed:15466165}. The disease is caused by variants affecting the gene represented in this entry.

NA

NA

2.7.1.21

3D-structure; ATP-binding; DNA synthesis; Early protein; Kinase; Nucleotide-binding; Reference proteome; Transferase

A,B

67808.8

624

0.07

43.94

6.1

-7.02

-6.27

DRD2

Homo sapiens (Human)

Dopamine receptor 2; D(2) dopamine receptor

G-protein coupled receptor 1 family

GPCR rhodopsin

Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase.

Congenital sucrase-isomaltase deficiency (CSID) [MIM:222900]: Autosomal recessive intestinal disorder that is clinically characterized by fermentative diarrhea, abdominal pain, and cramps upon ingestion of sugar. The symptoms are the consequence of absent or drastically reduced enzymatic activities of sucrase and isomaltase. The prevalence of CSID is 0.02 % in individuals of European descent and appears to be much higher in Greenland, Alaskan, and Canadian native people. CSID arises due to post-translational perturbations in the intracellular transport, polarized sorting, aberrant processing, and defective function of SI. {ECO:0000269|PubMed:10903344, ECO:0000269|PubMed:11340066, ECO:0000269|PubMed:14724820, ECO:0000269|PubMed:16329100, ECO:0000269|PubMed:8609217}. The disease is caused by variants affecting the gene represented in this entry.

DB01614; DB01063; DB01425; DB00915; DB06288; DB05964; DB00543; DB00182; DB04599; DB00714; DB01238; DB14185; DB09207; DB06216; DB04889; DB04888; DB05687; DB09223; DB04857; DB09128; DB01200; DB09018; DB00490; DB00248; DB06016; DB01038; DB00477; DB01239; DB00568; DB00363; DB01151; DB11274; DB13345; DB00320; DB01184; DB00988; DB00450; DB11275; DB01049; DB00696; DB01175; DB09194; DB00875; DB00623; DB04842; DB00502; DB04946; DB00458; DB04924; DB12579; DB01221; DB00555; DB01235; DB00589; DB00408; DB06077; DB08815; DB00934; DB09224; DB01043; DB00933; DB01403; DB01233; DB06148; DB00805; DB01618; DB08804; DB05766; DB00540; DB06229; DB00334; DB01267; DB12061; DB00715; DB01186; DB08922; DB00850; DB01100; DB09286; DB01621; DB12478; DB00413; DB00433; DB00420; DB01069; DB00777; DB01224; DB09097; DB12518; DB00409; DB00734; DB01549; DB00268; DB05271; DB06454; DB06144; DB00391; DB06477; DB04844; DB12093; DB00372; DB01622; DB00679; DB01623; DB13025; DB00831; DB00508; DB00726; DB06109; DB01392; DB00246; DB09225; DB01624

Q9NRI5; P14416; Q01959

NA

3D-structure; Alternative splicing; Cell membrane; Disulfide bond; G-protein coupled receptor; Glycoprotein; Golgi apparatus; Lipoprotein; Membrane; Palmitate; Receptor; Reference proteome; Transducer; Transmembrane; Transmembrane helix

B,C

24300.3

209

0.13

40.14

4.97

-7.83

-6.28

CAD

Homo sapiens (Human)

CAD

CarA family; CarB family; Metallo-dependent hydrolases superfamily, DHOase family, CAD subfamily; Aspartate/ornithine carbamoyltransferase superfamily, ATCase family

Carbon-nitrogen ligase

This protein is a "fusion" protein encoding four enzymatic activities of the pyrimidine pathway (GATase, CPSase, ATCase and DHOase).

Developmental and epileptic encephalopathy 50 (DEE50) [MIM:616457]: A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE50 is an autosomal recessive, progressive disease with onset in infancy and favorable response to treatment with oral uridine. {ECO:0000269|PubMed:25678555, ECO:0000269|PubMed:28087732}. The disease is caused by variants affecting the gene represented in this entry.

DB00128; DB00130; DB03459

P27708; Q8N137; P63104

NA

3D-structure; Acetylation; Allosteric enzyme; ATP-binding; Congenital disorder of glycosylation; Cytoplasm; Direct protein sequencing; Disease variant; Epilepsy; Hydrolase; Ligase; Magnesium; Manganese; Metal-binding; Multifunctional enzyme; Nucleotide-binding; Nucleus; Phosphoprotein; Proteomics identification; Pyrimidine biosynthesis; Reference proteome; Repeat; Transferase; Zinc

A

38268.4

351

0.06

41.29

5.86

-10.56

-6.27

ADORA2A

Homo sapiens (Human)

Adenosine receptor A2a; ADORA2; A2a Adenosine receptor; A(2A) adenosine receptor

G-protein coupled receptor 1 family

GPCR rhodopsin

The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. Receptor for adenosine.

Intellectual developmental disorder, autosomal recessive 59 (MRT59) [MIM:617323]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:26416544}. The disease is caused by variants affecting the gene represented in this entry.

DB08770; DB14132; DB00640; DB05009; DB05191; DB04853; DB00201; DB04932; DB09273; DB00651; DB00824; DB11757; DB17080; DB00555; DB00358; DB00683; DB01303; DB00806; DB06213; DB01412; DB00277

P30542; P29274; P29275; O15155; P21554; Q99418; O15354; Q7Z6G3; O43759-2; Q13107; Q5T9L3-1; P31424-1

NA

3D-structure; Cell membrane; Disulfide bond; G-protein coupled receptor; Glycoprotein; Membrane; Proteomics identification; Receptor; Reference proteome; Transducer; Transmembrane; Transmembrane helix; Ubl conjugation

A

32419.4

296

0.12

39.04

8.77

7.19

-6.28

cumD

Pseudomonas fluorescens

NA

NA

NA

Hydrolase

Hydrolase activity.

Intellectual developmental disorder, autosomal dominant 62 (MRD62) [MIM:618793]: An autosomal dominant form of intellectual disability, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD62 is characterized by mild to moderately impaired intellectual development. {ECO:0000269|PubMed:27479843, ECO:0000269|PubMed:29460436}. The disease is caused by variants affecting the gene represented in this entry.

DB03741; DB03793; DB03568; DB02531; DB03750; DB02406; DB03766

NA

NA

3D-structure; Hydrolase

A

30307.9

271

0.1

37.49

5.02

-11.58

-6.28

PTK6

Homo sapiens (Human)

Protein-tyrosine kinase 6; Breast tumor kinase; BRK

Protein kinase superfamily, Tyr protein kinase family, BRK/PTK6/SIK subfamily

Kinase

Non-receptor tyrosine-protein kinase implicated in the regulation of a variety of signaling pathways that control the differentiation and maintenance of normal epithelia, as well as tumor growth. Function seems to be context dependent and differ depending on cell type, as well as its intracellular localization. A number of potential nuclear and cytoplasmic substrates have been identified. These include the RNA-binding proteins: KHDRBS1/SAM68, KHDRBS2/SLM1, KHDRBS3/SLM2 and SFPQ/PSF; transcription factors: STAT3 and STAT5A/B and a variety of signaling molecules: ARHGAP35/p190RhoGAP, PXN/paxillin, BTK/ATK, STAP2/BKS. Associates also with a variety of proteins that are likely upstream of PTK6 in various signaling pathways, or for which PTK6 may play an adapter-like role. These proteins include ADAM15, EGFR, ERBB2, ERBB3 and IRS4. In normal or non-tumorigenic tissues, PTK6 promotes cellular differentiation and apoptosis. In tumors PTK6 contributes to cancer progression by sensitizing cells to mitogenic signals and enhancing proliferation, anchorage-independent survival and migration/invasion. Association with EGFR, ERBB2, ERBB3 may contribute to mammary tumor development and growth through enhancement of EGF-induced signaling via BTK/AKT and PI3 kinase. Contributes to migration and proliferation by contributing to EGF-mediated phosphorylation of ARHGAP35/p190RhoGAP, which promotes association with RASA1/p120RasGAP, inactivating RhoA while activating RAS. EGF stimulation resulted in phosphorylation of PNX/Paxillin by PTK6 and activation of RAC1 via CRK/CrKII, thereby promoting migration and invasion. PTK6 activates STAT3 and STAT5B to promote proliferation. Nuclear PTK6 may be important for regulating growth in normal epithelia, while cytoplasmic PTK6 might activate oncogenic signaling pathways.

Periodic paralysis hypokalemic 1 (HOKPP1) [MIM:170400]: An autosomal dominant disorder manifested by episodic flaccid generalized muscle weakness associated with falls of serum potassium levels. {ECO:0000269|PubMed:17418573, ECO:0000269|PubMed:18162704, ECO:0000269|PubMed:19118277, ECO:0000269|PubMed:7987325, ECO:0000269|PubMed:8004673}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Malignant hyperthermia 5 (MHS5) [MIM:601887]: Autosomal dominant disorder that is potentially lethal in susceptible individuals on exposure to commonly used inhalational anesthetics and depolarizing muscle relaxants. {ECO:0000269|PubMed:9199552}. Disease susceptibility is associated with variants affecting the gene represented in this entry.; DISEASE: Thyrotoxic periodic paralysis 1 (TTPP1) [MIM:188580]: A sporadic muscular disorder characterized by episodic weakness and hypokalemia during a thyrotoxic state. It is clinically similar to hereditary hypokalemic periodic paralysis, except for the fact that hyperthyroidism is an absolute requirement for disease manifestation. The disease presents with recurrent episodes of acute muscular weakness of the four extremities that vary in severity from paresis to complete paralysis. Attacks are triggered by ingestion of a high carbohydrate load or strenuous physical activity followed by a period of rest. Thyrotoxic periodic paralysis can occur in association with any cause of hyperthyroidism, but is most commonly associated with Graves disease. {ECO:0000269|PubMed:15001631}. Disease susceptibility is associated with variants affecting the gene represented in this entry.; DISEASE: Congenital myopathy 18 (CMYO18) [MIM:620246]: A congenital myopathy of variable severity, ranging from severe fetal akinesia to milder forms of muscle weakness. Most affected individuals show delayed motor development with generalized hypotonia and progressive axial and limb muscle weakness beginning soon after birth or in infancy. Additional features may include swallowing difficulties, external ophthalmoplegia, ptosis, high-arched palate, and respiratory insufficiency. Muscle biopsy shows variable morphologic abnormalities, including alveolar changes in the intermyofibrillar network, fiber size variability, focal disorganization, internal nuclei, and dilated sarcoplasmic reticulum and T-tubules. CMYO18 inheritance is autosomal dominant or recessive. {ECO:0000269|PubMed:28012042, ECO:0000269|PubMed:31227654, ECO:0000269|PubMed:33060286}. The disease is caused by variants affecting the gene represented in this entry.

DB12010; DB11800; DB05294; DB15035

Q08043; Q3KP44; Q13191; Q16543; Q92841; Q8N9I9; Q5JST6; P04626; O00471; O14526; Q13480; P08238; P42858; Q9UKT9; Q5VWX1; Q5T5P2-6; P10721; O14770-4; Q13064; Q8TDC0; P78337; Q9NQX0; Q13882; Q04864; P23246; Q13239-3; O00401; Q9BYN7

EC 2.7.10.2

3D-structure; Alternative splicing; ATP-binding; Cell projection; Cytoplasm; Kinase; Membrane; Nucleotide-binding; Nucleus; Phosphoprotein; Proteomics identification; Reference proteome; SH2 domain; SH3 domain; Transferase; Tyrosine-protein kinase

A

30240.6

264

0.09

46.88

6.95

-0.14

-6.28

MTAP

Homo sapiens (Human)

Methylthioadenosine phosphorylase; MTAPase; MTA phosphorylase; MSAP; 5'-methylthioadenosine phosphorylase

PNP/MTAP phosphorylase family, MTAP subfamily

Glycosyltransferases

Involved in the breakdown of MTA, a major by-product of polyamine biosynthesis. Responsible for the first step in the methionine salvage pathway after MTA has been generated from S-adenosylmethionine. Has broad substrate specificity with 6-aminopurine nucleosides as preferred substrates. Catalyzes the reversible phosphorylation of S-methyl-5'-thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate.

Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMSMFH) [MIM:112250]: An autosomal dominant bone dysplasia characterized by pathologic fractures due to abnormal cortical growth and diaphyseal medullary stenosis. The fractures heal poorly, and there is progressive bowing of the lower extremities. Some patients show a limb-girdle myopathy, with muscle weakness and atrophy. Approximately 35% of affected individuals develop an aggressive form of bone sarcoma consistent with malignant fibrous histiocytoma or osteosarcoma. {ECO:0000269|PubMed:22464254}. The disease is caused by variants affecting the gene represented in this entry. DMSMFH causing mutations found in MTAP exon 9 result in exon skipping and dysregulated alternative splicing of all MTAP isoforms (PubMed:22464254). {ECO:0000269|PubMed:22464254}.; DISEASE: Loss of MTAP activity may play a role in human cancer. MTAP loss has been reported in a number of cancers, including osteosarcoma, malignant melanoma and gastric cancer.

DB02158; DB02933; DB02282; DB00173; DB02281

Q9H3R5; Q9P0I2

EC 2.4.2.28

3D-structure; Acetylation; Alternative splicing; Cytoplasm; Glycosyltransferase; Nucleus; Proteomics identification; Purine salvage; Reference proteome; Transferase

A

29538.9

268

0.06

40.97

7.18

0.36

-6.27

HDAC8

Homo sapiens (Human)

Histone deacetylase-8; HDACL1; HD8; CDA07

Histone deacetylase family, HD type 1 subfamily

Carbon-nitrogen hydrolase

Gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Also involved in the deacetylation of cohesin complex protein SMC3 regulating release of cohesin complexes from chromatin. May play a role in smooth muscle cell contractility. Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4).

Cornelia de Lange syndrome 5 (CDLS5) [MIM:300882]: A form of Cornelia de Lange syndrome, a clinically heterogeneous developmental disorder associated with malformations affecting multiple systems. It is characterized by facial dysmorphisms, abnormal hands and feet, growth delay, cognitive retardation, hirsutism, gastroesophageal dysfunction and cardiac, ophthalmologic and genitourinary anomalies. {ECO:0000269|PubMed:22885700, ECO:0000269|PubMed:22889856}. The disease is caused by variants affecting the gene represented in this entry.

DB07350; DB02565; DB07586; DB12565; DB05015; DB08168; DB01262; DB11841; DB14490; DB14491; DB14488; DB14501; DB14489; DB12645; DB01592; DB02917; DB06603; DB06819; DB03766; DB12847; DB06176; DB04297; DB00313; DB02546; DB01593; DB14487; DB14533; DB14548

NA

EC 3.5.1.98

3D-structure; Alternative splicing; Chromatin regulator; Chromosome; Cytoplasm; Disease variant; Hydrolase; Intellectual disability; Metal-binding; Nucleus; Obesity; Phosphoprotein; Proteomics identification; Reference proteome; Repressor; Transcription; Transcription regulation

A,B

39018.4

351

0.11

38.57

6.06

-5.26

-6.28

HCV NS5B

Hepatitis C virus genotype 1a (isolate 1) (HCV)

HCV NS5B; HCV p68

Hepacivirus polyprotein family

Peptidase

Core protein packages viral RNA to form a viral nucleocapsid, and promotes virion budding. Modulates viral translation initiation by interacting with HCV IRES and 40S ribosomal subunit. Also regulates many host cellular functions such as signaling pathways and apoptosis. Prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma signaling pathways and by inducing human STAT1 degradation. Thought to play a role in virus-mediated cell transformation leading to hepatocellular carcinomas. Interacts with, and activates STAT3 leading to cellular transformation. May repress the promoter of p53, and sequester CREB3 and SP110 isoform 3/Sp110b in the cytoplasm. Also represses cell cycle negative regulating factor CDKN1A, thereby interrupting an important check point of normal cell cycle regulation. Targets transcription factors involved in the regulation of inflammatory responses and in the immune response: suppresses NK-kappaB activation, and activates AP-1. Could mediate apoptotic pathways through association with TNF-type receptors TNFRSF1A and LTBR, although its effect on death receptor-induced apoptosis remains controversial. Enhances TRAIL mediated apoptosis, suggesting that it might play a role in immune-mediated liver cell injury. Seric core protein is able to bind C1QR1 at the T-cell surface, resulting in down-regulation of T-lymphocytes proliferation. May transactivate human MYC, Rous sarcoma virus LTR, and SV40 promoters. May suppress the human FOS and HIV-1 LTR activity. Alters lipid metabolism by interacting with hepatocellular proteins involved in lipid accumulation and storage. Core protein induces up-regulation of FAS promoter activity, and thereby probably contributes to the increased triglyceride accumulation in hepatocytes (steatosis) (By similarity).

Weaver syndrome (WVS) [MIM:277590]: A syndrome of accelerated growth and osseous maturation, unusual craniofacial appearance, hoarse and low-pitched cry, and hypertonia with camptodactyly. Distinguishing features of Weaver syndrome include broad forehead and face, ocular hypertelorism, prominent wide philtrum, micrognathia, deep horizontal chin groove, and deep-set nails. In addition, carpal bone development is advanced over the rest of the hand. {ECO:0000269|PubMed:22177091, ECO:0000269|PubMed:22190405, ECO:0000269|PubMed:23239504, ECO:0000269|PubMed:26694085, ECO:0000269|PubMed:28229514}. The disease is caused by variants affecting the gene represented in this entry.

DB05868; DB11779; DB07582; DB06058

Q91XE4; P42224; O00571

EC 2.7.7.48

3D-structure; Acetylation; Activation of host autophagy by virus; Apoptosis; ATP-binding; Capsid protein; Clathrin-mediated endocytosis of virus by host; Direct protein sequencing; Disulfide bond; Fusion of virus membrane with host endosomal membrane; Fusion of virus membrane with host membrane; G1/S host cell cycle checkpoint dysregulation by virus; Glycoprotein; Helicase; Host cell membrane; Host cytoplasm; Host endoplasmic reticulum; Host lipid droplet; Host membrane; Host mitochondrion; Host nucleus; Host-virus interaction; Hydrolase; Inhibition of host innate immune response by virus; Inhibition of host interferon signaling pathway by virus; Inhibition of host MAVS by virus; Inhibition of host RLR pathway by virus; Inhibition of host STAT1 by virus; Inhibition of host TRAFs by virus; Interferon antiviral system evasion; Ion channel; Ion transport; Lipoprotein; Magnesium; Membrane; Metal-binding; Modulation of host cell cycle by virus; Multifunctional enzyme; Nucleotide-binding; Nucleotidyltransferase; Oncogene; Palmitate; Phosphoprotein; Protease; Ribonucleoprotein; Ribosomal frameshifting; RNA-binding; RNA-directed RNA polymerase; Serine protease; SH3-binding; Thiol protease; Transcription; Transcription regulation; Transferase; Transmembrane; Transmembrane helix; Transport; Ubl conjugation; Viral attachment to host cell; Viral envelope protein; Viral immunoevasion; Viral ion channel; Viral nucleoprotein; Viral penetration into host cytoplasm; Viral RNA replication; Virion; Virus endocytosis by host; Virus entry into host cell; Zinc

A

61795.3

561

0.08

42.78

8.93

15.42

-6.27

Hae-influ nadR

Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd)

nadR; Transcriptional regulator nadR

Bacterial NMN adenylyltransferase family; Bacterial RNK family

Nicotinamide ribonucleoside uptake permease

This enzyme has twoactivities: nicotinamide mononucleotide (NMN) adenylyltransferase and ribosylnicotinamide (RN) kinase. The RN kinase activity catalyzes the phosphorylation of RN to form nicotinamide ribonucleotide. The NMN adenylyltransferase activity catalyzes the transfer of the AMP moiety of ATP to nicotinamide ribonucleotide to form NAD(+).

Involved in the epigenetic regulation of ESR1 expression in breast cancer in a TFAP2C, IFI16 and HDAC4/5/6-dependent manner. {ECO:0000269|PubMed:24413532}.

NA

NA

NA

3D-structure; Alternative initiation; ATP-binding; Cell membrane; Cytoplasm; Kinase; Membrane; Multifunctional enzyme; NAD; Nucleotide-binding; Pyridine nucleotide biosynthesis; Reference proteome; Transferase

A

39581.5

344

0.14

41.39

6.94

-0.18

-6.27

HMGCS1

Homo sapiens (Human)

Hydroxymethylglutaryl-CoA synthase, cytoplasmic; HMGCS; HMG-CoA synthase; 3-hydroxy-3-methylglutaryl coenzyme A synthase 1

Thiolase-like superfamily, HMG-CoA synthase family

NA

This enzyme condenses acetyl-CoA with acetoacetyl-CoA to form HMG-CoA, which is the substrate for HMG-CoA reductase.

Intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP) [MIM:617333]: An autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, delayed language, and facial dysmorphisms, most notably ptosis. Additional features may include poor growth, hypotonia, and seizures. {ECO:0000269|PubMed:27939639, ECO:0000269|PubMed:27939640}. The disease is caused by variants affecting the gene represented in this entry.

DB07740

O76082

EC 2.3.3.10

3D-structure; Acetylation; Cholesterol biosynthesis; Cholesterol metabolism; Cytoplasm; Lipid biosynthesis; Lipid metabolism; Phosphoprotein; Proteomics identification; Reference proteome; Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis; Sterol metabolism; Transferase

A

51328.4

462

0.11

24.44

5.33

-9.66

-6.28

TK1

Homo sapiens (Human)

Thymidine kinase, cytosolic

Thymidine kinase family

Kinase

cytosol, identical protein binding, thymidine kinase activity, zinc ion binding, DNA metabolic process, nucleobase-containing compound metabolic process, protein homotetramerization, pyrimidine nucleoside salvage, thymidine metabolic process

Seizures, benign familial infantile, 3 (BFIS3) [MIM:607745]: A form of benign familial infantile epilepsy, a neurologic disorder characterized by afebrile seizures occurring in clusters during the first year of life, without neurologic sequelae. BFIS3 inheritance is autosomal dominant. {ECO:0000269|PubMed:11371648, ECO:0000269|PubMed:12243921, ECO:0000269|PubMed:15048894, ECO:0000269|PubMed:16417554, ECO:0000269|PubMed:17021166, ECO:0000269|PubMed:17386050, ECO:0000269|PubMed:18479388, ECO:0000269|PubMed:20371507, ECO:0000269|PubMed:22612257, ECO:0000269|PubMed:23360469, ECO:0000269|PubMed:23758435, ECO:0000269|PubMed:25982755, ECO:0000269|PubMed:26291284, ECO:0000269|PubMed:29844171, ECO:0000269|PubMed:30144217}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Developmental and epileptic encephalopathy 11 (DEE11) [MIM:613721]: An autosomal dominant seizure disorder characterized by neonatal or infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities. Patients may progress to West syndrome, which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG. {ECO:0000269|PubMed:19783390, ECO:0000269|PubMed:19786696, ECO:0000269|PubMed:20956790, ECO:0000269|PubMed:22677033, ECO:0000269|PubMed:23033978, ECO:0000269|PubMed:23195492, ECO:0000269|PubMed:23550958, ECO:0000269|PubMed:23662938, ECO:0000269|PubMed:23708187, ECO:0000269|PubMed:23935176, ECO:0000269|PubMed:23988467, ECO:0000269|PubMed:24463883, ECO:0000269|PubMed:24579881, ECO:0000269|PubMed:24659627, ECO:0000269|PubMed:24710820, ECO:0000269|PubMed:25457084, ECO:0000269|PubMed:25459969, ECO:0000269|PubMed:25772804, ECO:0000269|PubMed:25818041, ECO:0000269|PubMed:26138355, ECO:0000269|PubMed:26291284, ECO:0000269|PubMed:26993267, ECO:0000269|PubMed:27864847, ECO:0000269|PubMed:29625812, ECO:0000269|PubMed:29844171, ECO:0000269|PubMed:30144217, ECO:0000269|PubMed:30415926}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Defects in SCN2A are associated with genetic epilepsy with febrile seizures plus (GEFS+), a familial autosomal dominant epilepsy syndrome, a clinical subset of febrile seizures, characterized by frequent episodes after 6 years of age and various types of subsequent epilepsy. {ECO:0000269|PubMed:29635106}.; DISEASE: Defects in SCN2A are associated with autism spectrum disorders (ASD). It seems that mutations resulting in sodium channel gain of function and increased neuron excitability lead to infantile seizures, whereas variants resulting in sodium channel loss of function and decrease neuron excitability are associated with ASD. {ECO:0000269|PubMed:28256214}.; DISEASE: Episodic ataxia 9 (EA9) [MIM:618924]: An autosomal dominant neurologic disorder characterized by episodic ataxia manifesting in the first years of life, early-onset seizures, difficulty walking, dizziness, slurred speech, headache, vomiting, and pain. The duration of ataxic episodes is heterogeneous. Most patients show episodes lasting minutes to maximum several hours, but periods lasting days up to weeks have been reported. Some patients have mildly delayed development with speech delay and/or autistic features or mildly impaired intellectual development. {ECO:0000269|PubMed:26645390, ECO:0000269|PubMed:27159988, ECO:0000269|PubMed:27328862, ECO:0000269|PubMed:28065826}. The disease is caused by variants affecting the gene represented in this entry.

DB01692; DB04485; DB02452; DB00432; DB00495

P05067; A0A087WZT3; Q92993; Q1RN33; P04183

EC 2.7.1.21

3D-structure; Acetylation; ATP-binding; Cytoplasm; DNA synthesis; Kinase; Metal-binding; Nucleotide-binding; Phosphoprotein; Proteomics identification; Reference proteome; Transferase; Ubl conjugation; Zinc

A

19373.5

174

0.09

36.21

8.63

3.88

-6.28

CTSD

Homo sapiens (Human)

CPSD; CD

Peptidase A1 family

Peptidase

Plays a role in APP processing following cleavage and activation by ADAM30 which leads to APP degradation. Involved in the pathogenesis of several diseases such as breast cancer and possibly Alzheimer disease. Acid protease active in intracellular protein breakdown.

Ceroid lipofuscinosis, neuronal, 10 (CLN10) [MIM:610127]: A form of neuronal ceroid lipofuscinosis with onset at birth or early childhood. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy. {ECO:0000269|PubMed:16670177, ECO:0000269|PubMed:16685649, ECO:0000269|PubMed:21990111}. The disease is caused by variants affecting the gene represented in this entry.

DB03028; DB03096; DB07542; DB08740; DB02216

P05067; Q9P1A6-3; I6L9I8; Q9H6S3; Q7Z602; P28799; PRO_0000012695 [P28799]; PRO_0000012696 [P28799]; PRO_0000012697 [P28799]; PRO_0000012698 [P28799]; PRO_0000012699 [P28799]; PRO_0000012700 [P28799]; PRO_0000012701 [P28799]; P68431; Q9Y6F6-3; Q12756; Q5TA79; Q86VF5-3; O15130-2; Q96LB9; P09565; Q9C004; Q8NBJ7; Q9BQG1; P28347-2; P45880; Q15007-2; O00308; Q5W0Z9-4; Q6ZNH5

EC 3.4.23.5

3D-structure; Alzheimer disease; Aspartyl protease; Direct protein sequencing; Disease variant; Disulfide bond; Glycoprotein; Hydrolase; Lysosome; Neurodegeneration; Neuronal ceroid lipofuscinosis; Protease; Proteomics identification; Reference proteome; Secreted; Signal; Zymogen

A,B

37264.2

341

0.1

32.32

5.6

-4.86

-6.27

HRAS

Homo sapiens (Human)

p21ras; cHras; c-H-ras; Transforming protein p21; HaRas; Ha-Ras; H-Ras-1; GTPase HRas, Nterminally processed

Small GTPase superfamily, Ras family

Small GTPase

Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Involved in the activation of Ras protein signal transduction.

Costello syndrome (CSTLO) [MIM:218040]: A rare condition characterized by prenatally increased growth, postnatal growth deficiency, intellectual disability, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy and/or atrial tachycardia), tumor predisposition, skin and musculoskeletal abnormalities. {ECO:0000269|PubMed:16170316, ECO:0000269|PubMed:16329078, ECO:0000269|PubMed:16443854, ECO:0000269|PubMed:17054105, ECO:0000269|PubMed:18039947, ECO:0000269|PubMed:18247425, ECO:0000269|PubMed:19995790}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Congenital myopathy with excess of muscle spindles (CMEMS) [MIM:218040]: Variant of Costello syndrome. {ECO:0000269|PubMed:17412879}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Thyroid cancer, non-medullary, 2 (NMTC2) [MIM:188470]: A form of non-medullary thyroid cancer (NMTC), a cancer characterized by tumors originating from the thyroid follicular cells. NMTCs represent approximately 95% of all cases of thyroid cancer and are classified into papillary, follicular, Hurthle cell, and anaplastic neoplasms. {ECO:0000269|PubMed:12727991}. Disease susceptibility is associated with variants affecting the gene represented in this entry.; DISEASE: Mutations which change positions 12, 13 or 61 activate the potential of HRAS to transform cultured cells and are implicated in a variety of human tumors. {ECO:0000269|PubMed:3670300}.; DISEASE: Bladder cancer (BLC) [MIM:109800]: A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas that begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences. {ECO:0000269|PubMed:6298635, ECO:0000269|PubMed:6844927}. Disease susceptibility is associated with variants affecting the gene represented in this entry.; DISEASE: Schimmelpenning-Feuerstein-Mims syndrome (SFM) [MIM:163200]: A disease characterized by sebaceous nevi, often on the face, associated with variable ipsilateral abnormalities of the central nervous system, ocular anomalies, and skeletal defects. Many oral manifestations have been reported, not only including hypoplastic and malformed teeth, and mucosal papillomatosis, but also ankyloglossia, hemihyperplastic tongue, intraoral nevus, giant cell granuloma, ameloblastoma, bone cysts, follicular cysts, oligodontia, and odontodysplasia. Sebaceous nevi follow the lines of Blaschko and these can continue as linear intraoral lesions, as in mucosal papillomatosis. {ECO:0000269|PubMed:22683711}. The disease is caused by variants affecting the gene represented in this entry.

DB04315; DB04137; DB02210; DB08751; DB03226; DB15588

Q99996-3; P53677-2; P10398; Q9NXL2-1; Q9UII2; Q9H7T9; Q00994; Q9H2G9; P15056; Q7Z569; Q5PSV4; Q9ULD4-2; Q96LL4; Q96HB5; Q49A88-3; Q96GN5-2; P24941; O95674; Q9H3R5; Q9Y4F5-3; Q86XR8; Q494V2-2; Q8WUX9; Q14117; Q9Y6W6; O14641; A0AVK6; Q8NB25; Q8IZU1; O94868-3; P15407; P15408; P52655; Q96CS2; Q9BT25; Q8IV36; O43248; Q53GQ0; P10809; Q8NDH6-2; Q8IY31-2; Q8NA54; Q13352; P28290-2; Q9BVG8-5; Q2M2Z5; Q6P597; P57682; Q9UH77; P08727; Q14525; Q14847-2; Q96LR2; P27338; Q99558; Q96EZ8; Q8TAC0; Q5JXC2; Q8NEH6; Q9Y605; Q96HT8; Q9GZM8; P21359; Q8N5V2; Q6PHZ7; Q9BZ95-3; A5D8V7; O43482; Q9BR81; O15534; Q9BUL5; O00329; O00329-2; Q9UPR0; Q96I34; Q15435-3; P04049; P11233; Q15311; Q12967; Q9NS23-2; Q9NS23-4; Q8WWW0; Q8TBY0; Q9P2K3-2; Q9NZL6; O15211; Q8IXN7; Q13671; Q13671-1; Q8WVD3; Q9BY12-3; Q13435; Q12824; Q13573; Q07889; Q86W54-2; Q92783-2; O75886; Q13586; Q8N4C7; O75528; P54274-2; Q9BXU0; Q5T0J7-2; Q5T1C6; Q8IUR5-4; P36406; Q86WT6-2; Q99598; Q6PF05; Q9UGJ1-2; Q9Y5Z9; P22415; Q495M9; Q9H270; Q8NEZ2; P19544-6; O43829; Q9C0F3; Q7Z637; Q86V28; P42337; Q9Z0S9; Q9EQZ6; P27671; Q5EBH1; Q5EBH1-1; P52306-5

NA

3D-structure; Acetylation; Alternative splicing; Cell membrane; Cytoplasm; Direct protein sequencing; Disease variant; Glycoprotein; Golgi apparatus; GTP-binding; Hydrolase; Isopeptide bond; Lipoprotein; Membrane; Methylation; Nucleotide-binding; Nucleus; Palmitate; Prenylation; Proteomics identification; Proto-oncogene; Reference proteome; S-nitrosylation; Ubl conjugation

E,F

28737.2

259

0.1

30.69

5.64

-4.15

-6.27

LCN2

Homo sapiens (Human)

p25; Siderocalin LCN2; Oncogene 24p3; NGAL; Lipocalin-2; LCN2; 25 kDa alpha-2-microglobulin-related subunit of MMP-9

Calycin superfamily, Lipocalin family

Calycin family

Iron-trafficking protein involved in multiple processes such as apoptosis, innate immunity and renal development. Binds iron through association with 2,5-dihydroxybenzoic acid (2,5- DHBA), a siderophore that shares structural similarities withbacterial enterobactin, and delivers or removes iron from the cell, depending on the context. Iron-bound form (holo-24p3) is internalized following binding to the SLC22A17 (24p3R) receptor, leading to release of iron and subsequent increase of intracellular iron concentration. In contrast, association of the iron-free form (apo-24p3) with the SLC22A17 (24p3R) receptor is followed by association with an intracellular siderophore, iron chelation and iron transfer to the extracellular medium, thereby reducing intracellular iron concentration. Involved in apoptosis due to interleukin-3 (IL3) deprivation: iron-loaded form increases intracellular iron concentration without promoting apoptosis, while iron-free form decreases intracellular iron levels, inducing expression of the proapoptotic protein BCL2L11/BIM, resulting in apoptosis. Involved in innate immunity, possibly by sequestrating iron, leading to limit bacterial growth. .

Pseudovaginal perineoscrotal hypospadias (PPSH) [MIM:264600]: A form of male pseudohermaphroditism in which 46,XY males show ambiguous genitalia at birth, including perineal hypospadias and a blind perineal pouch, and develop masculinization at puberty. The name of the disorder stems from the finding of a blind-ending perineal opening resembling a vagina and a severely hypospadiac penis with the urethra opening onto the perineum. {ECO:0000269|PubMed:10718838, ECO:0000269|PubMed:10898110, ECO:0000269|PubMed:10999800, ECO:0000269|PubMed:12843198, ECO:0000269|PubMed:15064320, ECO:0000269|PubMed:1522235, ECO:0000269|PubMed:15528927, ECO:0000269|PubMed:15770495, ECO:0000269|PubMed:16098368, ECO:0000269|PubMed:16181229, ECO:0000269|PubMed:7554313, ECO:0000269|PubMed:8626825, ECO:0000269|PubMed:8768837, ECO:0000269|PubMed:9208814, ECO:0000269|PubMed:9745434, ECO:0000269|PubMed:9843052}. The disease is caused by variants affecting the gene represented in this entry.

DB02710; DB01672; DB01926; DB04043; DB01631; DB04476

P49419-2; Q9NXW9; Q8WXI3; Q12797-6; Q9BXY8; Q96LC9; P49069; P24863; Q9UKJ5; Q9H1P6; Q9H6B4; O14595; Q08426; Q6NZ36-4; B3EWG5; Q7Z4H3; Q6ISS4; Q5TA76; P80188; Q9UIQ6-2; Q9Y6Y9; Q96JG8; Q8IXL7-2; Q969H8; Q969S2; Q17RF5; P07237; P13667; Q96FA3; Q9NRD5; Q13526; Q9UGP5-2; Q12837; P54646; Q86Y79; O60895; Q9BWG6; P60059; O43765; Q96EQ0; Q8IYX1; Q9UL33-2; P20396; O43715; Q13049; Q99816; Q5W5X9-3; Q99757; P57075-2; Q969M7; Q9UMX0; Q9UHD9; P15692-12; Q14119; Q9Y6T4; Q9H0D6; O96006; A0A1U9X8X8

NA

3D-structure; Alternative splicing; Apoptosis; Cytoplasmic vesicle; Direct protein sequencing; Disulfide bond; Glycoprotein; Immunity; Innate immunity; Ion transport; Iron; Iron transport; Proteomics identification; Pyrrolidone carboxylic acid; Reference proteome; Secreted; Signal; Transport

A

19748.4

172

0.13

30.73

7.71

0.72

-6.28

FDFT1

Homo sapiens (Human)

Squalene synthase; SS; SQS; Farnesyl-diphosphate farnesyltransferase; FPP:FPP farnesyltransferase

Phytoene/squalene synthase family

Alkyl aryl transferase

Participates in the isoprenoid biosynthetic pathway, catalyzing a two-step reaction in which two identical molecules of farnesyl pyrophosphate (FPP) are converted into squalene, with the consumption of NADPH.

Squalene synthase deficiency (SQSD) [MIM:618156]: An autosomal recessive disorder characterized by profound developmental delay, brain abnormalities, 2/3 syndactyly of the toes, facial dysmorphisms, low total and LDL-cholesterol, and abnormal urine organic acids. {ECO:0000269|PubMed:29909962}. The disease is caused by variants affecting the gene represented in this entry.

DB05317

Q13520; Q3SXY8; P04233-2; P11912; O75503; O43889-2; Q9GZR5; Q5JX71; P48165; Q8TDT2; Q8N5M9; Q6IBW4-4; Q96RD7; Q14973; Q9NQQ7-3; Q96MV1; Q9Y320

EC 2.5.1.21

3D-structure; Alternative splicing; Cholesterol biosynthesis; Cholesterol metabolism; Endoplasmic reticulum; Lipid biosynthesis; Lipid metabolism; Magnesium; Membrane; Metal-binding; Multifunctional enzyme; NAD; NADP; Proteomics identification; Reference proteome; Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis; Sterol metabolism; Transferase; Transmembrane; Transmembrane helix

A

37860

329

0.1

40.19

5.47

-7.65

-6.27

CSNK1E

Homo sapiens (Human)

Casein kinase I isoform epsilon; CKIe; CKI-epsilon

Protein kinase superfamily, CK1 Ser/Thr protein kinase family, Casein kinase I subfamily

Kinase

Can phosphorylate a large number of proteins. Participates in Wnt signaling. Phosphorylates DVL1 and DVL2. Central component of the circadian clock. In balance with PP1, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. Controls PER1 and PER2 nuclear transport and degradation. Inhibits cytokine-induced granuloytic differentiation. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates.

Truncation of the 3'-untranslated (3'-UTR) region of CD274 transcripts leads to elevated expression of CD274 in multiple cancers including T-cell leukemia, diffuse large B-cell lymphoma and stomach adenocarcinoma (PubMed:27281199). Disruption of 3'-UTR region is caused by structural variants that stabilize CD274 transcripts, leading to overexpression (PubMed:27281199). Increased expression in tumors promotes immune evasion and tumor cell growth by allowing malignant cells to escape destruction by the immune system (PubMed:27281199). {ECO:0000269|PubMed:27281199}.

DB06195; DB14989

P25054; O15169; O14640; O14641; Q92997; Q9BQ89; Q1W6H9; Q86UY5; P08238; P23508; Q00987; Q16625; O15055; O75382; P62258; Q04917; Q5T7W0; O70239; Q60838

EC 2.7.11.1

3D-structure; ATP-binding; Biological rhythms; Cytoplasm; Kinase; Methylation; Nucleotide-binding; Nucleus; Phosphoprotein; Proteomics identification; Reference proteome; Serine/threonine-protein kinase; Transferase

A

32897.6

284

0.13

40.77

9.3

11.34

-6.28

phrB

Escherichia coli (strain K12)

NA

phr;b0708;JW0698

DNA photolyase class-1 family

Lyase (carbon-carbon)

Deoxyribodipyrimidine photo-lyase activity.DNA binding.Nucleotide binding.

Severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-negative/NK-cell-negative due to adenosine deaminase deficiency (ADASCID) [MIM:102700]: An autosomal recessive disorder accounting for about 50% of non-X-linked SCIDs. SCID refers to a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients with SCID present in infancy with recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. ADA deficiency has been diagnosed in chronically ill teenagers and adults (late or adult onset). Population and newborn screening programs have also identified several healthy individuals with normal immunity who have partial ADA deficiency. {ECO:0000269|PubMed:10200056, ECO:0000269|PubMed:1284479, ECO:0000269|PubMed:2166947, ECO:0000269|PubMed:2783588, ECO:0000269|PubMed:3182793, ECO:0000269|PubMed:3839802, ECO:0000269|PubMed:6208479, ECO:0000269|PubMed:7599635, ECO:0000269|PubMed:8227344, ECO:0000269|PubMed:8299233, ECO:0000269|PubMed:9361033}. The disease is caused by variants affecting the gene represented in this entry.

DB03147

P68739

4.1.99.3

3D-structure; Chromophore; DNA damage; DNA repair; DNA-binding; FAD; Flavoprotein; Lyase; Nucleotide-binding; Reference proteome

A,B

53349.8

469

0.1

42.46

6.57

-2.28

-6.26

CDK4

Homo sapiens (Human)

NA

NA

Protein kinase superfamily, CMGC Ser/Thr protein kinase family, CDC2/CDKX subfamily

Cell cycle

ATP binding.Cyclin binding.Cyclin-dependent protein serine/threonine kinase activity.Cyclin-dependent protein serine/threonine kinase regulator activity.Protein complex binding.

Melanoma, cutaneous malignant 3 (CMM3) [MIM:609048]: A malignant neoplasm of melanocytes, arising de novo or from a pre-existing benign nevus, which occurs most often in the skin but may also involve other sites. {ECO:0000269|PubMed:7652577, ECO:0000269|PubMed:8528263, ECO:0000269|PubMed:9311594, ECO:0000269|PubMed:9425228}. Disease susceptibility is associated with variants affecting the gene represented in this entry.

DB12001; DB03496; DB12010; DB09073; DB02733; DB11730; DB15442

Q9UH17; P24385; P30279; P30281; Q16543; P50613; P38936; P46527; P49918; P42771; P42772; P42773; P55273; Q9UJC3; P08238; Q9UKT9; Q0VD86; P01106; Q9ULD0; P28749; Q08999; P09936; Q8N720

2.7.11.22

3D-structure; Acetylation; Alternative splicing; ATP-binding; Cell cycle; Cell division; Cytoplasm; Disease variant; Kinase; Membrane; Nucleotide-binding; Nucleus; Phosphoprotein; Proteomics identification; Reference proteome; Serine/threonine-protein kinase; Transferase

B

30138.4

267

0.09

36.2

5.78

-5.83

-6.27

DLD

Homo sapiens (Human)

NA

PHE3;LAD;GCSL

Class-I pyridine nucleotide-disulfide oxidoreductase family

Oxidoreductase

Dihydrolipoyl dehydrogenase activity.Electron carrier activity.Flavin adenine dinucleotide binding.Lipoamide binding.NAD binding.

Dihydrolipoamide dehydrogenase deficiency (DLDD) [MIM:246900]: An autosomal recessive metabolic disorder characterized biochemically by a combined deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), pyruvate dehydrogenase complex (PDC), and alpha-ketoglutarate dehydrogenase complex (KGDC). Clinically, affected individuals have lactic acidosis and neurologic deterioration due to sensitivity of the central nervous system to defects in oxidative metabolism. {ECO:0000269|PubMed:10448086, ECO:0000269|PubMed:11687750, ECO:0000269|PubMed:12925875, ECO:0000269|PubMed:15712224, ECO:0000269|PubMed:16442803, ECO:0000269|PubMed:16770810, ECO:0000269|PubMed:17404228, ECO:0000269|PubMed:20160912, ECO:0000269|PubMed:8506365, ECO:0000269|PubMed:8968745, ECO:0000269|PubMed:9540846, ECO:0000269|PubMed:9934985}. The disease is caused by variants affecting the gene represented in this entry.

DB03147; DB00145; DB00157

P42858; O14713; O00330; P30041; P62258

1.8.1.4

3D-structure; Acetylation; Alternative splicing; Cell projection; Cilium; Cytoplasmic vesicle; Disease variant; Disulfide bond; FAD; Flagellum; Flavoprotein; Mitochondrion; NAD; Nucleus; Oxidoreductase; Phosphoprotein; Proteomics identification; Redox-active center; Reference proteome; Transit peptide

A,B,C,D,E,F,G,H

49832.7

471

0.06

26.19

6.51

-2.02

-6.26