DPP9

Homo sapiens (Human)

Dipeptidyl peptidase-like protein 9; Dipeptidyl peptidase IX; Dipeptidyl peptidase IV-related protein 2; DPRP2; DPRP-2; DPP IX; DPLP9; DP9

Peptidase S9B family, DPPIV subfamily

Peptidase

Dipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2.

Hatipoglu immunodeficiency syndrome (HATIS) [MIM:620331]: An autosomal recessive immunologic disorder manifesting in infancy or early childhood, and characterized by failure to thrive, short stature, skin pigmentation abnormalities, pancytopenia, and susceptibility to recurrent infections. {ECO:0000269|PubMed:36112693}. The disease is caused by variants affecting the gene represented in this entry.

NA

Q9NXR5; Q86TI2; Q6NUP5; P46379-2; Q8WUW1; Q96A83-2; O75190-2; O14645; Q01658; P29692-2; Q06787-7; Q9Y5Q9; O14901; Q9BVL2; Q96CV9; Q06830; P14678-2; P49458; Q11203; Q13148; P14927

EC 3.4.14.5

3D-structure; Acetylation; Alternative splicing; Aminopeptidase; Cytoplasm; Disease variant; Hydrolase; Nucleus; Protease; Proteomics identification; Reference proteome; Serine protease

A

92797.4

808

0.12

37.45

6.34

-8.98

-6.92

MAP3K14

Homo sapiens (Human)

NIK; NF-kappa-beta-inducing kinase; Mitogen-activated protein kinase kinase kinase 14; HsNIK

Protein kinase superfamily, STE Ser/Thr protein kinase family, MAP kinase kinase kinase subfamily

Kinase

Promotes proteolytic processing of NFKB2/P100, which leads to activation of NF-kappa-B via the non-canonical pathway. Could act in a receptor-selective manner. Lymphotoxin beta-activated kinase which seems to be exclusively involved in the activation of NF-kappa-B and its transcriptional activity.

Immunodeficiency 112 (IMD112) [MIM:620449]: An autosomal recessive, primary immunologic disorder characterized by variable abnormalities affecting lymphoid immunity, including hypogammaglobulinemia, lymphopenia or paradoxical lymphocytosis, and recurrent bacterial, viral, and fungal infections. {ECO:0000269|PubMed:25406581, ECO:0000269|PubMed:29230214}. The disease is caused by variants affecting the gene represented in this entry.

NA

Q16543; O15111; P01112; P07900; P08238; O14920; Q9Y6K9; Q14974; P36578; Q02878; P62917; P62280; P62277; Q12933; Q13114; P62258; Q60680-2

EC 2.7.11.25

3D-structure; ATP-binding; Cytoplasm; Disease variant; Kinase; Nucleotide-binding; Phosphoprotein; Proteomics identification; Reference proteome; Serine/threonine-protein kinase; Transferase; Ubl conjugation

A

36970.9

335

0.07

41.12

6.18

-5.06

-6.91

nfsA

Escherichia coli (strain K12)

NA

mda18;b0851;mdaA;ybjB;JW0835

Flavin oxidoreductase frp family

Oxidoreductase

Chromate reductase activity.FMN binding.Oxidoreductase activity, acting on NAD(P)H, nitrogenous group as acceptor.

Multiple fibroadenomas of the breast (MFAB) [MIM:615554]: A benign breast disease marked by lobuloalveolar growth with abnormally high proliferation of the epithelium, and characterized by the presence of more than 3 fibroadenomas in one breast. Fibroadenomas are adenomas containing fibrous tissue. {ECO:0000269|PubMed:18779591}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Hyperprolactinemia (HPRL) [MIM:615555]: A disorder characterized by increased levels of prolactin in the blood not associated with gestation or the puerperium. HPRL may result in infertility, hypogonadism, and galactorrhea. {ECO:0000269|PubMed:24195502}. The disease is caused by variants affecting the gene represented in this entry.

DB03247; DB00698

P28630

1.-.-.-

3D-structure; Flavoprotein; FMN; NADP; Oxidoreductase; Reference proteome

A,B

53582.7

480

0.07

45.43

6.47

-3.13

-6.9

ASL

Homo sapiens (Human)

NA

NA

Lyase 1 family, Argininosuccinate lyase subfamily

Lyase

Argininosuccinate lyase activity.Identical protein binding.

Argininosuccinic aciduria (ARGINSA) [MIM:207900]: An autosomal recessive disorder of the urea cycle. The disease is characterized by mental and physical retardation, liver enlargement, skin lesions, dry and brittle hair showing trichorrhexis nodosa microscopically and fluorescing red, convulsions, and episodic unconsciousness. {ECO:0000269|PubMed:11747432, ECO:0000269|PubMed:11747433, ECO:0000269|PubMed:12408190, ECO:0000269|PubMed:1705937, ECO:0000269|PubMed:17326097, ECO:0000269|PubMed:19703900, ECO:0000269|PubMed:22081021, ECO:0000269|PubMed:2263616, ECO:0000269|PubMed:24166829, ECO:0000269|PubMed:9045711}. The disease is caused by variants affecting the gene represented in this entry. The phenotype heterogeneity among patients is associated with interallelic complementation resulting in either complete loss of activity or partial regeneration of functional active sites in the heterotetrameric mutant protein. {ECO:0000269|PubMed:11747433}.

DB03814; DB00125; DB02267

P04424; Q9BTE3-2; Q96HA8; O75382

4.3.2.1

3D-structure; Acetylation; Alternative splicing; Amino-acid biosynthesis; Arginine biosynthesis; Disease variant; Lyase; Proteomics identification; Reference proteome; Urea cycle

A,B

51364.1

459

0.08

35.82

6.66

-1.25

-6.9

MT-CO2

Homo sapiens (Human)

NA

MTCO2;COXII;COII;COX2

Cytochrome c oxidase subunit 2 family

Immune system

Copper ion binding.Cytochrome-c oxidase activity.

Mitochondrial complex IV deficiency (MT-C4D) [MIM:220110]: A disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Features include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development and intellectual disability. Some affected individuals manifest a fatal hypertrophic cardiomyopathy resulting in neonatal death. A subset of patients manifest Leigh syndrome. {ECO:0000269|PubMed:10486321}. The disease is caused by variants affecting the gene represented in this entry.

DB02659; DB04464; DB05412

Q9NZ94-2; P49281-3

7.1.1.9

3D-structure; Copper; Disease variant; Electron transport; Magnesium; Membrane; Metal-binding; Mitochondrion; Mitochondrion inner membrane; Primary mitochondrial disease; Proteomics identification; Reference proteome; Respiratory chain; Translocase; Transmembrane; Transmembrane helix; Transport

C

21687.9

189

0.11

38

5.68

-3.26

-6.9

MT-CYB

Bos taurus (Bovine)

NA

CYTB;MTCYB;COB

Cytochrome b family

NA

Component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex) that is part of the mitochondrial respiratory chain. The b-c1 complex mediates electron transfer from ubiquinol to cytochrome c. Contributes to the generation of a proton gradient across the mitochondrial membrane that is then used for ATP synthesis. {ECO:0000269|PubMed:1327781, ECO:0000269|PubMed:20025846, ECO:0000269|PubMed:9485330, ECO:0000305|PubMed:189810}."

Combined oxidative phosphorylation deficiency 6 (COXPD6) [MIM:300816]: A mitochondrial disease resulting in a neurodegenerative disorder characterized by psychomotor delay, hypotonia, areflexia, muscle weakness and wasting. Some patients manifest prenatal ventriculomegaly and severe postnatal encephalomyopathy. {ECO:0000269|PubMed:20362274, ECO:0000269|PubMed:22019070, ECO:0000269|PubMed:25583628, ECO:0000269|PubMed:26004228, ECO:0000269|PubMed:26173962, ECO:0000269|PubMed:27178839}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease, X-linked recessive, 4, with or without cerebellar ataxia (CMTX4) [MIM:310490]: A neuromuscular disorder characterized by progressive sensorimotor axonal neuropathy, distal sensory impairment, difficulty walking due to peripheral neuropathy and/or cerebellar ataxia, and deafness due to auditory neuropathy. Additional features include cognitive impairment, cerebellar atrophy, dysarthria, abnormal extraocular movements, tremor, dysmetria and spasticity. The age at onset ranges from infancy to young adulthood. {ECO:0000269|PubMed:23217327, ECO:0000269|PubMed:26004228}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Deafness, X-linked, 5, with peripheral neuropathy (DFNX5) [MIM:300614]: A form of hearing loss characterized by absent or severely abnormal auditory brainstem response, abnormal middle ear reflexes, abnormal speech discrimination, loss of outer hair cell function, and cochlear nerve hypoplasia. DFNX5 patients manifest auditory neuropathy with childhood onset, associated with distal sensory impairment affecting the peripheral nervous system. {ECO:0000269|PubMed:25986071}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy (SEMDHL) [MIM:300232]: An X-linked recessive developmental disorder characterized by slowly progressive skeletal and neurologic abnormalities, including short stature, large and deformed joints, significant motor impairment, visual defects, and sometimes cognitive deficits. Affected individuals typically have normal early development in the first year or so of life, followed by development regression and the development of symptoms. Brain imaging shows white matter abnormalities consistent with hypomyelinating leukodystrophy. {ECO:0000269|PubMed:28842795}. The disease is caused by variants affecting the gene represented in this entry.

NA

NA

NA

3D-structure; Electron transport; Heme; Iron; Membrane; Metal-binding; Mitochondrion; Mitochondrion inner membrane; Reference proteome; Respiratory chain; Transmembrane; Transmembrane helix; Transport; Ubiquinone

C,D,F,G,H

99281.2

866

0.12

43.81

8.32

7.12

-6.9

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

-6.9

NOS3

Homo sapiens (Human)

Nitric oxide synthase, endothelial; NOSIII; NOS,type III; NOS type III; Endothelial nitric oxide synthase; Endothelial NOS; ENOS; EC-NOS; Constitutive NOS; CNOS

NOS family

Paired donor oxygen oxidoreductase

NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets. Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway.

Variation Asp-298 in NOS3 may be associated with susceptibility to coronary spasm. {ECO:0000269|PubMed:11740345, ECO:0000269|PubMed:9737779}.

DB07001; DB02048; DB02911; DB02335; DB01997; DB03332; DB04534; DB07244; DB03100; DB03918; DB02207; DB03065; DB00125; DB02994; DB01833; DB00155; DB00997; DB07388; DB03974; DB02077; DB01821; DB09237; DB01110; DB03144; DB03305; DB01686; DB04559; DB02044; DB08019; DB08018; DB02027; DB02979; DB00435; DB04223; DB06154; DB03910; DB02141; DB03963; DB03707; DB02234; DB04018; DB00360; DB02589

P60709; P63010-2; Q8N6T3-3; Q9Y575-3; Q96FT7-4; Q5SZD1; Q16543; Q9UNS2; Q8IUI8; P35222; Q05193; O15287; Q08379; Q71DI3; P69905; P61978; Q12891; Q9UKT9; Q9Y2M5; Q14525; Q6DKI2; P43364-2; Q8N6F8; O94851; A4FUJ8; Q8N594; Q8IVI9; Q6X4W1-6; O15381-5; Q9NV79; Q16549; Q5T2W1; O75925; Q96I34; Q6ZMI0-5; P57052; Q9GZR2; Q96D59; Q8N6K7-2; Q9GZS3; Q8IUW3; Q7Z699; Q7Z698; P50502; Q9BR01-2; Q9NVV9; Q86WT6-2; Q9H347; P58304; Q9NZC7-5; Q9UNY5; P14079

EC 1.14.13.39

3D-structure; Alternative splicing; Calcium; Calmodulin-binding; Cell membrane; Cytoplasm; Cytoskeleton; Direct protein sequencing; FAD; Flavoprotein; FMN; Golgi apparatus; Heme; Iron; Lipoprotein; Membrane; Metal-binding; Myristate; NADP; Oxidoreductase; Palmitate; Phosphoprotein; Proteomics identification; Reference proteome; Zinc

A,B

90790.1

803

0.11

50.67

6.03

-9.56

-6.91

SDHB

Sus scrofa (Pig)

NA

NA

Succinate dehydrogenase/fumarate reductase iron-sulfur protein family

NA

Iron-sulfur protein (IP) subunit of the succinate dehydrogenase complex (mitochondrial respiratory chain complex II), responsible for transferring electrons from succinate to ubiquinone (coenzyme Q) (PubMed:15989954). SDH also oxidizes malate to the non-canonical enol form of oxaloacetate, enol-oxaloacetate. Enol-oxaloacetate, which is a potent inhibitor of the succinate dehydrogenase activity, is further isomerized into keto-oxaloacetate (By similarity). {ECO:0000250|UniProtKB:Q3T189, ECO:0000269|PubMed:15989954}."

A chromosomal aberration involving NFKB2 is found in a case of B-cell non Hodgkin lymphoma (B-NHL). Translocation t(10;14)(q24;q32) with IGHA1. The resulting oncogene is also called Lyt-10C alpha variant.; DISEASE: A chromosomal aberration involving NFKB2 is found in a cutaneous T-cell leukemia (C-TCL) cell line. This rearrangement produces the p80HT gene which codes for a truncated 80 kDa protein (p80HT).; DISEASE: In B-cell leukemia (B-CLL) cell line, LB40 and EB308, can be found after heterogeneous chromosomal aberrations, such as internal deletions.; DISEASE: Immunodeficiency, common variable, 10 (CVID10) [MIM:615577]: A primary immunodeficiency characterized by childhood-onset of recurrent infections, hypogammaglobulinemia, and decreased numbers of memory and marginal zone B-cells. Some patients may develop autoimmune features and have circulating autoantibodies. An unusual feature is central adrenal insufficiency. {ECO:0000269|PubMed:24140114, ECO:0000269|PubMed:25524009}. The disease is caused by variants affecting the gene represented in this entry.

NA

NA

1.1.5.-; 1.3.5.1

2Fe-2S; 3D-structure; 3Fe-4S; 4Fe-4S; Acetylation; Electron transport; Iron; Iron-sulfur; Membrane; Metal-binding; Mitochondrion; Mitochondrion inner membrane; Oxidoreductase; Reference proteome; Transit peptide; Transport; Tricarboxylic acid cycle

A,B,C,D

120840

1092

0.09

39.34

7.64

4.11

-6.9

ACACA

Homo sapiens (Human)

NA

ACAC;ACCA;ACC1

NA

Ligase

Acetyl-CoA carboxylase activity.ATP binding.Biotin carboxylase activity.Identical protein binding.Metal ion binding.

Acetyl-CoA carboxylase-alpha deficiency (ACACAD) [MIM:613933]: An autosomal recessive inborn error of de novo fatty acid synthesis associated with severe brain damage, persistent myopathy and poor growth. {ECO:0000269|PubMed:6114432}. The disease is caused by variants affecting the gene represented in this entry.

DB00121

Q13085; O60218; P38398; Q96EB6; Q9CQ20; P02654; Q92915-2; Q6NTF9-3

6.4.1.2

3D-structure; Acetylation; Allosteric enzyme; Alternative promoter usage; ATP-binding; Biotin; Cytoplasm; Direct protein sequencing; Fatty acid biosynthesis; Fatty acid metabolism; Ligase; Lipid biosynthesis; Lipid metabolism; Magnesium; Manganese; Metal-binding; Multifunctional enzyme; Nucleotide-binding; Phosphoprotein; Proteomics identification; Reference proteome

A,B

54237.7

486

0.09

39.18

6.37

-2.46

-6.9

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

-6.91

MAP2K1

Homo sapiens (Human)

PRKMK1; Mitogen-activated protein kinase kinase 1; MKK1; MEK 1; MAPKK 1; MAPK/ERKkinase 1; MAPK/ERK kinase 1; MAP kinase kinase 1; Dual specificity mitogen-activated protein kinase kinase 1

Protein kinase superfamily, STE Ser/Thr protein kinase family, MAP kinase kinase subfamily

Kinase

Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis. Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway.

Cardiofaciocutaneous syndrome 3 (CFC3) [MIM:615279]: A form of cardiofaciocutaneous syndrome, a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects and intellectual disability. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. Distinctive features of CFC3 include macrostomia and horizontal shape of palpebral fissures. {ECO:0000269|PubMed:16439621, ECO:0000269|PubMed:18042262}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Melorheostosis, isolated (MEL) [MIM:155950]: A sclerosing bone disorder characterized by hyperostosis of the cortex of tubular bones, frequently involving one limb. The lesions may be accompanied by abnormalities of adjacent soft tissue, joint contractures, sclerodermatous skin lesions, muscle atrophy, or hemangioma. {ECO:0000269|PubMed:29643386}. The disease is caused by variants affecting the gene represented in this entry.

DB06892; DB07046; DB08208; DB03115; DB11967; DB06616; DB05239; DB02152; DB07101; DB08130; DB14904; DB11689; DB08911

Q8N9N5; Q8N9N5-2; Q9NR09; P15056; Q9Y297; O15519-1; P28482; P27361; Q13526; Q9H8W4; P04049; Q8WWU5-7; Q86Y07; Q86Y07-1; P46937

EC 2.7.12.2

3D-structure; Acetylation; Alternative splicing; ATP-binding; Cardiomyopathy; Cytoplasm; Cytoskeleton; Direct protein sequencing; Disease variant; Ectodermal dysplasia; Intellectual disability; Kinase; Membrane; Nucleotide-binding; Nucleus; Phosphoprotein; Proteomics identification; Reference proteome; Serine/threonine-protein kinase; Transferase; Tyrosine-protein kinase

B

34785.9

311

0.07

46.58

6.29

-2.54

-6.9

CHRNA2

Homo sapiens (Human)

CHRNA2

Ligand-gated ion channel (TC 1.A.9) family, Acetylcholine receptor (TC 1.A.9.1) subfamily, Alpha-2/CHRNA2 sub-subfamily

Neurotransmitter receptor

After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.

Epilepsy, nocturnal frontal lobe, 4 (ENFL4) [MIM:610353]: An autosomal dominant focal epilepsy characterized by nocturnal seizures associated with fear sensation, tongue movements, and nocturnal wandering, closely resembling nightmares and sleep walking. {ECO:0000269|PubMed:16826524}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Seizures, benign familial infantile, 6 (BFIS6) [MIM:610353]: 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. BFIS6 inheritance is autosomal dominant. {ECO:0000269|PubMed:25847220}. The disease may be caused by variants affecting the gene represented in this entry.

DB00732; DB00237; DB00411; DB00565; DB01245; DB00514; DB01135; DB07720; DB00898; DB00472; DB00483; DB08960; DB00657; DB01336; DB00416; DB01226; DB00184; DB01337; DB01338; DB00721; DB00728; DB05740; DB00202; DB01199; DB01339

NA

NA

3D-structure; Alternative splicing; Cell membrane; Disease variant; Disulfide bond; Epilepsy; Glycoprotein; Ion channel; Ion transport; Ligand-gated ion channel; Membrane; Postsynaptic cell membrane; Proteomics identification; Receptor; Reference proteome; Signal; Synapse; Transmembrane; Transmembrane helix; Transport

A,B

48323.4

413

0.15

32

5.69

-6.58

-6.91

CHRNA3-CHRNB4

Homo sapiens (Human)

Neuronal acetylcholine receptor

Ligand-gated ion channel (TC 1.A.9) family, Acetylcholine receptor (TC 1.A.9.1) subfamily, Alpha-3/CHRNA3 sub-subfamily

Neurotransmitter receptor

A type of nicotinic acetylcholine receptor, consisting of 3 and 4 subunits.

Bladder dysfunction, autonomic, with impaired pupillary reflex and secondary CAKUT (BAIPRCK) [MIM:191800]: An autosomal recessive disease characterized by impaired innervation and autonomic dysfunction of the urinary bladder, hydronephrosis, vesicoureteral reflux, small kidneys, recurrent urinary tract infections, and progressive renal insufficiency. Additional autonomic features are impaired pupillary reflex and orthostatic hypotension. The disease manifests in utero or early childhood. {ECO:0000269|PubMed:31708116}. The disease is caused by variants affecting the gene represented in this entry.

DB00915; DB01156; DB00237; DB00565; DB09028; DB00514; DB07720; DB00898; DB00472; DB05710; DB01227; DB00848; DB00333; DB00184; DB01090; DB00202; DB01273

NA

NA

3D-structure; Alternative splicing; Cell membrane; Disease variant; Disulfide bond; Endoplasmic reticulum; Glycoprotein; Golgi apparatus; Ion channel; Ion transport; Ligand-gated ion channel; Membrane; Phosphoprotein; Postsynaptic cell membrane; Proteomics identification; Receptor; Reference proteome; Signal; Synapse; Transmembrane; Transmembrane helix; Transport; Ubl conjugation

A,B

89661.2

775

0.12

35.11

6.07

-5.67

-6.9

CACNA1I

Homo sapiens (Human)

Voltage-gated calcium channel subunit alpha Cav3.3; Voltage-dependent T-type calcium channel subunit alpha-1I; KIAA1120; Ca(v)3.3

Calcium channel alpha-1 subunit (TC 1.A.1.11) family, CACNA1I subfamily

Voltage-gated ion channel

Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. This channel gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by nickel and mibefradil. A particularity of this type of channels is an opening at quite negative potentials, and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes. Gates in voltage ranges similar to, but higher than alpha 1G or alpha 1H (By similarity).

Neurodevelopmental disorder with speech impairment and with or without seizures (NEDSIS) [MIM:620114]: An autosomal dominant disorder with variable manifestations. Severely affected individuals have profound global developmental delay, hypotonia, delayed or absent walking, absent speech, feeding difficulties, cortical visual impairment, and onset of hyperexcitability and seizures in the first months or years of life. Some patients manifest a milder phenotype characterized by mild to moderate cognitive impairment and mild speech delay, usually without seizures. {ECO:0000269|PubMed:33704440}. The disease is caused by variants affecting the gene represented in this entry.

DB01118; DB00381; DB09231; DB13746; DB11148; DB11093; DB11348; DB14481; DB09061; DB00568; DB09235; DB00228; DB00153; DB04841; DB09238; DB14009; DB01388; DB14011; DB00622; DB01115; DB06712; DB06152; DB00617; DB09498; DB09089; DB00661; DB00909

Q8NEC5; Q96P56

NA

3D-structure; Alternative splicing; Calcium; Calcium channel; Calcium transport; Disease variant; Glycoprotein; Intellectual disability; Ion channel; Ion transport; Membrane; Phosphoprotein; Proteomics identification; Reference proteome; Repeat; Transmembrane; Transmembrane helix; Transport; Voltage-gated channel

A

130104

1135

0.12

41.15

8.25

8.02

-6.91

MKNK1

Homo sapiens (Human)

Mnk1; MAP kinase signal-integrating kinase 1

Protein kinase superfamily, CAMK Ser/Thr protein kinase family

Protein kinase superfamily. CAMK Ser/Thr protein kinase family

May play a role in the response to environmental stress and cytokines. Appears to regulate translation by phosphorylating EIF4E, thus increasing the affinity of this protein for the 7-methylguanosine-containing mRNA cap.

Defects in MELK are associated with some cancers, such as brain or breast cancers. Expression is dramatically increased in aggressive undifferentiated tumors, correlating with poor patient outcome in breast and brain cancers, suggesting a role in tumor-initiating cells and proliferation via its function in cell proliferation regulation.

DB12010

P54253; Q03060-25; P42858; P28482; Q16539; Q96CV9

EC 2.7.11.1

3D-structure; Alternative splicing; ATP-binding; Cytoplasm; Kinase; Magnesium; Metal-binding; Nucleotide-binding; Nucleus; Phosphoprotein; Proteomics identification; Reference proteome; Serine/threonine-protein kinase; Transferase; Translation regulation

A

27536.2

241

0.11

50.42

6.02

-3.43

-6.9

qacR

Staphylococcus aureus

NA

SAP104C_022;SAP100B_005

NA

Transcription

DNA binding.Transcription factor activity, sequence-specific DNA binding.

Pigmentary disorder, reticulate, with systemic manifestations, X-linked (PDR) [MIM:301220]: An X-linked recessive disorder characterized by recurrent infections and sterile inflammation in various organs. Diffuse skin hyperpigmentation with a distinctive reticulate pattern is universally evident by early childhood. This is later followed in many patients by hypohidrosis, corneal inflammation and scarring, enterocolitis that resembles inflammatory bowel disease, and recurrent urethral strictures. Melanin and amyloid deposition is present in the dermis. Affected males also have a characteristic facies with frontally upswept hair and flared eyebrows. Female carriers have only restricted pigmentary changes along Blaschko's lines. {ECO:0000269|PubMed:27019227}. The disease is caused by variants affecting the gene represented in this entry. XLPDR is caused by a recurrent intronic mutation that results in missplicing and reduced POLA1 expression. This leads to a decrease in cytosolic RNA:DNA hybrids and constitutive activation of type I interferon responses, but has no effect on cell replication. {ECO:0000269|PubMed:27019227}.; DISEASE: Van Esch-O'Driscoll syndrome (VEODS) [MIM:301030]: An X-linked recessive syndrome characterized by different degrees of intellectual disability, moderate to severe short stature, microcephaly, hypogonadism, and variable congenital malformations. {ECO:0000269|PubMed:31006512}. The disease is caused by variants affecting the gene represented in this entry.

DB04209; DB03608; DB03808; DB01123

NA

NA

3D-structure; Direct protein sequencing; DNA-binding; Plasmid; Repressor; Transcription; Transcription regulation

A,B,D,E

43715

372

0.13

34.92

8.24

2.33

-6.88

RARB

Homo sapiens (Human)

RAR-epsilon; RAR-beta; Nuclear receptor subfamily 1 group B member 2; NR1B2; HBV-activated protein; HAP

Nuclear hormone receptor family, NR1 subfamily

Nuclear hormone receptor

Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence or presence of hormone ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function. Receptor for retinoic acid.

Microphthalmia, syndromic, 12 (MCOPS12) [MIM:615524]: A form of microphthalmia, a disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues (anophthalmia). In many cases, microphthalmia/anophthalmia occurs in association with syndromes that include non-ocular abnormalities. MCOPS12 patients manifest variable features, including diaphragmatic hernia, pulmonary hypoplasia, and cardiac abnormalities. {ECO:0000269|PubMed:24075189, ECO:0000269|PubMed:27120018}. The disease is caused by variants affecting the gene represented in this entry.

DB00459; DB00210; DB00523; DB02877; DB00926; DB05785; DB04942; DB00799; DB00755; DB12808

O95273; P50222; Q9UBK2; P62195; P28702; P28702-3; P48443; P03255

NA

3D-structure; Alternative splicing; Cytoplasm; Disease variant; DNA-binding; Metal-binding; Microphthalmia; Nucleus; Phosphoprotein; Proto-oncogene; Receptor; Reference proteome; Transcription; Transcription regulation; Zinc; Zinc-finger

A,B

25904.1

229

0.06

44.34

7.55

0.73

-6.89

CHRNA1

Homo sapiens (Human)

NA

ACHRA;CHNRA

Ligand-gated ion channel (TC 1.A.9) family, Acetylcholine receptor (TC 1.A.9.1) subfamily, Alpha-1/CHRNA1 sub-subfamily

Immune system

Acetylcholine binding.Acetylcholine-gated cation-selective channel activity.Acetylcholine receptor activity.Ion channel activity.Ligand-gated ion channel activity.

Multiple pterygium syndrome, lethal type (LMPS) [MIM:253290]: Multiple pterygia are found infrequently in children with arthrogryposis and in fetuses with fetal akinesia syndrome. In lethal multiple pterygium syndrome there is intrauterine growth retardation, multiple pterygia, and flexion contractures causing severe arthrogryposis and fetal akinesia. Subcutaneous edema can be severe, causing fetal hydrops with cystic hygroma and lung hypoplasia. Oligohydramnios and facial anomalies are frequent. {ECO:0000269|PubMed:18252226}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: The alpha subunit is the main focus for antibody binding in myasthenia gravis. Myasthenia gravis is characterized by sporadic muscular fatigability and weakness, occurring chiefly in muscles innervated by cranial nerves, and characteristically improved by cholinesterase-inhibiting drugs.; DISEASE: Myasthenic syndrome, congenital, 1A, slow-channel (CMS1A) [MIM:601462]: A common congenital myasthenic syndrome. Congenital myasthenic syndromes are characterized by muscle weakness affecting the axial and limb muscles (with hypotonia in early-onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. CMS1A is a slow-channel myasthenic syndrome. It is caused by kinetic abnormalities of the AChR, resulting in prolonged AChR channel opening episodes, prolonged endplate currents, and depolarization block. This is associated with calcium overload, which may contribute to subsequent degeneration of the endplate and postsynaptic membrane. {ECO:0000269|PubMed:16685696, ECO:0000269|PubMed:7619526, ECO:0000269|PubMed:8872460, ECO:0000269|PubMed:9158151, ECO:0000269|PubMed:9221765}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Myasthenic syndrome, congenital, 1B, fast-channel (CMS1B) [MIM:608930]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness affecting the axial and limb muscles (with hypotonia in early-onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. CMS1B is a fast-channel myasthenic syndrome. It is caused by kinetic abnormalities of the AChR, resulting in brief opening and activity of the channel, with a rapid decay in endplate current, failure to achieve threshold depolarization of the endplate and consequent failure to fire an action potential. {ECO:0000269|PubMed:10195214, ECO:0000269|PubMed:12588888, ECO:0000269|PubMed:15079006}. The disease is caused by variants affecting the gene represented in this entry.

DB08838; DB00565; DB00555

NA

NA

3D-structure; Alternative splicing; Cell membrane; Congenital myasthenic syndrome; Direct protein sequencing; Disease variant; Disulfide bond; Glycoprotein; Ion channel; Ion transport; Ligand-gated ion channel; Membrane; Postsynaptic cell membrane; Proteomics identification; Receptor; Reference proteome; Signal; Synapse; Transmembrane; Transmembrane helix; Transport

A,B,C,D,E

46717.8

411

0.11

38.02

4.77

-22.31

-6.89

treA

Escherichia coli (strain K12)

NA

JW1186;osmA;b1197

Glycosyl hydrolase 37 family

NA

Provides the cells with the ability to utilize trehalose at high osmolarity by splitting it into glucose molecules that can subsequently be taken up by the phosphotransferase-mediated uptake system.

SRC kinase activity has been shown to be increased in several tumor tissues and tumor cell lines such as colon carcinoma cells. {ECO:0000269|PubMed:2498394, ECO:0000269|PubMed:3093483}.; DISEASE: Thrombocytopenia 6 (THC6) [MIM:616937]: A form of thrombocytopenia, a hematologic disorder defined by a decrease in the number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting. THC6 is an autosomal dominant form. Affected individuals may also have bone abnormalities and an increased risk for myelofibrosis. {ECO:0000269|PubMed:26936507}. The disease is caused by variants affecting the gene represented in this entry.

NA

NA

3.2.1.28

3D-structure; Direct protein sequencing; Glycosidase; Hydrolase; Periplasm; Reference proteome; Signal

A

57508.9

507

0.11

48.32

5.48

-10.13

-6.89