UNC5C

Summary

UNC5C (unc-5 netrin receptor C, HGNC:12569) is a protein-coding gene on chromosome 4q22.3, encoding Netrin receptor UNC5C (O95185). Receptor for netrin required for axon guidance.

This gene product belongs to the UNC-5 family of netrin receptors. Netrins are secreted proteins that direct axon extension and cell migration during neural development. They are bifunctional proteins that act as attractants for some cell types and as repellents for others, and these opposite actions are thought to be mediated by two classes of receptors. The UNC-5 family of receptors mediate the repellent response to netrin; they are transmembrane proteins containing 2 immunoglobulin (Ig)-like domains and 2 type I thrombospondin motifs in the extracellular region.

Source: NCBI Gene 8633 — RefSeq curated summary.

At a glance

• GWAS associations: 17
• Clinical variants (ClinVar): 129 total
• MANE Select transcript: NM_003728

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12569
Approved symbol	UNC5C
Name	unc-5 netrin receptor C
Location	4q22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000182168
Ensembl biotype	protein_coding
OMIM	603610
Entrez	8633

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000453304, ENST00000504962, ENST00000506749, ENST00000513796

RefSeq mRNA: 1 — MANE Select: NM_003728 NM_003728

CCDS: CCDS3643

Canonical transcript exons

ENST00000453304 — 16 exons

Exon	Start	End
ENSE00001291369	95219985	95220176
ENSE00001294689	95335410	95335631
ENSE00001296559	95218969	95219313
ENSE00001298838	95278259	95278362
ENSE00001305606	95250487	95250667
ENSE00001309274	95242429	95242593
ENSE00001316821	95301606	95301749
ENSE00001327179	95244977	95245144
ENSE00001591928	95202731	95202964
ENSE00001622435	95185047	95185196
ENSE00001659763	95162504	95169399
ENSE00001746003	95182897	95183061
ENSE00001757047	95170154	95170332
ENSE00001774811	95206628	95206796
ENSE00002159302	95216124	95216211
ENSE00003849916	95548734	95548973

Expression profiles

Bgee: expression breadth ubiquitous, 202 present calls, max score 88.91.

FANTOM5 (CAGE): breadth broad, TPM avg 7.3211 / max 488.4674, expressed in 644 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53201	3.1207	500
53205	2.0788	375
53202	0.9310	415
53207	0.5301	199
53203	0.4005	183
53204	0.1873	93
53206	0.0726	34

Top tissues by expression

289 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	88.91	gold quality
tibia	UBERON:0000979	87.55	gold quality
medial globus pallidus	UBERON:0002477	83.36	gold quality
pons	UBERON:0000988	81.94	gold quality
inferior vagus X ganglion	UBERON:0005363	81.86	gold quality
globus pallidus	UBERON:0001875	81.55	gold quality
subthalamic nucleus	UBERON:0001906	78.80	gold quality
adrenal tissue	UBERON:0018303	78.61	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.31	silver quality
right coronary artery	UBERON:0001625	77.29	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	77.12	gold quality
spinal cord	UBERON:0002240	76.53	gold quality
dorsal plus ventral thalamus	UBERON:0001897	76.49	gold quality
superior vestibular nucleus	UBERON:0007227	76.22	gold quality
thyroid gland	UBERON:0002046	76.15	gold quality
left coronary artery	UBERON:0001626	76.11	gold quality
adrenal gland	UBERON:0002369	76.05	gold quality
lateral nuclear group of thalamus	UBERON:0002736	75.98	silver quality
right adrenal gland cortex	UBERON:0035827	75.96	gold quality
ventral tegmental area	UBERON:0002691	75.94	gold quality
popliteal artery	UBERON:0002250	75.78	gold quality
tibial artery	UBERON:0007610	75.74	gold quality
coronary artery	UBERON:0001621	75.73	gold quality
left lobe of thyroid gland	UBERON:0001120	75.72	gold quality
left adrenal gland cortex	UBERON:0035825	75.68	gold quality
adrenal cortex	UBERON:0001235	75.60	gold quality
right lobe of thyroid gland	UBERON:0001119	75.53	gold quality
right adrenal gland	UBERON:0001233	75.48	gold quality
left adrenal gland	UBERON:0001234	75.38	gold quality
medulla oblongata	UBERON:0001896	75.22	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	2899.56
E-HCAD-35	yes	102.52
E-HCAD-25	yes	55.80
E-CURD-119	yes	26.87
E-GEOD-125970	yes	14.07
E-CURD-10	no	18.85
E-ANND-3	no	6.14

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PAX6

miRNA regulators (miRDB)

312 targeting UNC5C, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-340-5P	100.00	72.50	4437
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684

Literature-anchored findings (GeneRIF, showing 28)

• may represent tumor suppressor that inhibit tumor extension outside the region of netrin-1 availability by inducing apoptosis (PMID:12655055)
• Netrin binds through multiple domains to both DCC and Unc5c. in Caenorhabditis elegans indicate that both netrin binding and nonbinding domains are necessary for phenotypic rescue of an unc-5 loss of function mutation. (PMID:15574733)
• The loss of UNC5C expression observed in human colorectal cancer is a selective advantage for tumor progression (PMID:17967459)
• study provides evidence that most colorectal cancers have alterations in both UNC5C and DCC netrin receptors; while UNC5C expression is regulated primarily via epigenetic regulation, DCC defects are mediated through allelic deletions (PMID:18054557)
• Aberrant methylation of the netrin-1 receptor genes UNC5C and DCC detected in advanced colorectal cancer. (PMID:19242752)
• UNC5C might act as a tumor suppressor and UNC5C methylation might present a malignant potential in colorectal cancer. (PMID:19331160)
• Stronger expression of UNC5B and UNC5C receptors in synovial fibroblasts might contribute to the disordered phenotype of rheumatoid arthritis and osteoarthritis. (PMID:19822088)
• UNC5C methylation was observed in the course of gastric carcinogenesis and disappeared in highly advanced gastric carcinomas. (PMID:20032384)
• UNC5C acts as a tumour suppressor in RCC and is down-regulated in RCC. Loss of heterozygosity and DNA methylation contribute to the inactivation of UNC5C in renal cell carcinoma. (PMID:21600761)
• Inherited mutations in UNC5C prevent apoptosis and increase risk of colorectal cancer. (PMID:21893118)
• knockdown of DSCAM inhibits netrin-induced tyrosine phosphorylation of UNC5C and Fyn as well as the interaction of UNC5C with Fyn. The double knockdown of both receptors abolishes the induction of Fyn tyrosine phosphorylation by netrin-1 (PMID:22685302)
• TNM stage 1 hepatocellular carcinoma (HCC) presented UNC5C methylation, indicating that the UNC5C gene has been methylated from the early stages of HCC. (PMID:23178624)
• UNC5C mutations are very rare in familial and sporadic colorectal carcinomas. (PMID:24415873)
• The rare coding variant might not play an important role in AD risk in mainland China. (PMID:24866402)
• we have identified novel frequent somatic mutations of UNC5C in muscle-invasive bladder cancers. (PMID:25316812)
• T835M (rs137875858) in the UNC5C was associated with late-onset Alzheimer disease and increased cell death in HEK293 cells. (PMID:25419706)
• The objective of this study is to investigate the influence of UNC5C loci on the neuroimaging of strategic regions of Alzheimer’s disease. (PMID:26660111)
• 7 of these 8 variants do not cause increased colorectal cancer risk, including UNC5C c.1882_1883delinsAA (p.A628K). (PMID:26852919)
• identify the V-2 domain of netrin-1 to be important for its interaction with the Ig1/Ig2 domains of UNC5H2 (PMID:26859457)
• Data show that overexpression of wild-type netrin receptor UNC5C (UNC5C) causes low-grade death, which is intensified by an Alzheimer Disease-linked mutation T835M, and mediated by amyloid beta precursor protein (APP). (PMID:27068745)
• the results suggest that UNC5C methylation may be an earlier event in the development of colorectal cancer, which was negatively correlated with protein expression. (PMID:28378635)
• we identified ENC1 and UNC5C as genes with convergent genetic, epigenetic, and transcriptomic evidence supporting a potential role in the dissociation of cognition and neuropathology in an aging population. (PMID:28441426)
• Promoter Hypermethylation of UNC5C Gene is associated with Colorectal Cancer. (PMID:29801399)
• An UNC5C Allele Predicts Cognitive Decline and Hippocampal Atrophy in Clinically Normal Older Adults. (PMID:30883345)
• UNC5Cknockdown enhances the growth and metastasis of breast cancer cells by potentiating the integrin alpha6/beta4 signaling pathway. (PMID:31789389)
• A global integrated analysis of UNC5C down-regulation in cancers: insights from mechanism and combined treatment strategy. (PMID:33706130)
• Identification and validation of HOXD3 and UNC5C as molecular signatures in keloid based on weighted gene co-expression network analysis. (PMID:35709926)
• UNC5C: Novel Gene Associated with Psychiatric Disorders Impacts Dysregulation of Axon Guidance Pathways. (PMID:38540364)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	unc5cb	ENSDARG00000087341
danio_rerio	unc5ca	ENSDARG00000099133
mus_musculus	Unc5c	ENSMUSG00000059921
rattus_norvegicus	Unc5c	ENSRNOG00000029071
drosophila_melanogaster	unc-5	FBGN0034013
caenorhabditis_elegans		WBGENE00006745

Paralogs (4): UNC5B (ENSG00000107731), UNC5A (ENSG00000113763), UNC5CL (ENSG00000124602), UNC5D (ENSG00000156687)

Protein

Protein identifiers

Netrin receptor UNC5C — O95185 (reviewed: O95185)

Alternative names: Protein unc-5 homolog 3, Protein unc-5 homolog C

All UniProt accessions (3): O95185, D6RE16, E0CX15

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for netrin required for axon guidance. Mediates axon repulsion of neuronal growth cones in the developing nervous system upon ligand binding. NTN1/Netrin-1 binding might cause dissociation of UNC5C from polymerized TUBB3 in microtubules and thereby lead to increased microtubule dynamics and axon repulsion. Axon repulsion in growth cones may also be caused by its association with DCC that may trigger signaling for repulsion. Might also collaborate with DSCAM in NTN1-mediated axon repulsion independently of DCC. Also involved in corticospinal tract axon guidance independently of DCC. Involved in dorsal root ganglion axon projection towards the spinal cord. It also acts as a dependence receptor required for apoptosis induction when not associated with netrin ligand.

Subunit / interactions. Interacts with DCC (via cytoplasmic domain). Interacts (tyrosine phosphorylated form) with PTPN11. Interacts (via extracellular domain) with FLRT3 (via extracellular domain). Interacts (via Ig-like C2-type domain) with DSCAM (via extracellular domain). Interacts (via death domain) with DAPK1. Interacts (via cytoplasmic domain) with TUBB3; this interaction is decreased by NTN1/Netrin-1.

Subcellular location. Cell membrane. Cell surface. Synapse. Synaptosome. Cell projection. Axon. Dendrite. Growth cone. Lamellipodium. Filopodium.

Tissue specificity. Mainly expressed in brain. Expressed in temporal lobe cortical neurons and in neurons of the hippocampal pyramidal layer. Also expressed in kidney. Not expressed in developing or adult lung.

Post-translational modifications. Proteolytically cleaved by caspases during apoptosis. The cleavage does not take place when the receptor is associated with netrin ligand. Its cleavage by caspases is required to induce apoptosis. Phosphorylated on different cytoplasmic tyrosine residues. Phosphorylation of Tyr-568 leads to an interaction with PTPN11 phosphatase, suggesting that its activity is regulated by phosphorylation/dephosphorylation. Tyrosine phosphorylation is netrin-dependent.

Disease relevance. Alzheimer disease (AD) [MIM:104300] Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. Disease susceptibility may be associated with variants affecting the gene represented in this entry.

Miscellaneous. Down-regulated in multiple cancers including colorectal, breast, ovary, uterus, stomach, lung, or kidney cancers.

Similarity. Belongs to the unc-5 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O95185-1	1	yes
O95185-2	2

RefSeq proteins (1): NP_003719* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000488	Death_dom	Domain
IPR000884	TSP1_rpt	Repeat
IPR000906	ZU5_dom	Domain
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR013098	Ig_I-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR033772	UPA	Domain
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR037936	UNC5A-D	Family
IPR042154	Death_UNC5C	Domain
IPR057755	UNC5A-D-like_N	Domain

Pfam: PF00090, PF00531, PF00791, PF07679, PF17217, PF25609

UniProt features (36 total): disulfide bond 9, domain 6, sequence variant 4, sequence conflict 3, region of interest 2, modified residue 2, glycosylation site 2, topological domain 2, splice variant 2, signal peptide 1, chain 1, site 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95185-F1	78.72	0.54

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 415–416 (cleavage; by caspase-3)

Post-translational modifications (2): 502, 568

Disulfide bonds (9): 83–144, 95–142, 188–239, 272–309, 276–313, 287–299, 328–362, 332–367, 340–352

Glycosylation sites (2): 236, 361

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-418886	Netrin mediated repulsion signals

MSigDB gene sets: 220 (showing top): BENPORATH_ES_WITH_H3K27ME3, PID_NETRIN_PATHWAY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOCC_CELL_SURFACE, GOBP_NEUROGENESIS, GTACAGG_MIR486, CTAGGAA_MIR384, GOBP_TAXIS, ZIC1_01, TGACATY_UNKNOWN, GOBP_HEAD_DEVELOPMENT, MAF_Q6, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, SABATES_COLORECTAL_ADENOMA_DN, chr4q22

GO Biological Process (14): apoptotic process (GO:0006915), axon guidance (GO:0007411), brain development (GO:0007420), anterior/posterior axon guidance (GO:0033564), ectopic germ cell programmed cell death (GO:0035234), positive regulation of apoptotic process (GO:0043065), positive regulation of developmental process (GO:0051094), chemorepulsion of axon (GO:0061643), dorsal root ganglion development (GO:1990791), positive regulation of reproductive process (GO:2000243), regulation of neuron migration (GO:2001222), signal transduction (GO:0007165), regulation of cell migration (GO:0030334), netrin-activated signaling pathway (GO:0038007)

GO Molecular Function (5): netrin receptor activity (GO:0005042), netrin receptor activity involved in chemorepulsion (GO:0005043), tubulin binding (GO:0015631), protein kinase binding (GO:0019901), protein binding (GO:0005515)

GO Cellular Component (12): plasma membrane (GO:0005886), cell surface (GO:0009986), lamellipodium (GO:0030027), filopodium (GO:0030175), dendrite (GO:0030425), growth cone (GO:0030426), neuronal cell body (GO:0043025), synapse (GO:0045202), membrane (GO:0016020), axon (GO:0030424), cell projection (GO:0042995), neuron projection (GO:0043005)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Netrin-1 signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
axon guidance	2
positive regulation of biological process	2
negative chemotaxis	2
plasma membrane bounded cell projection	2
neuron projection	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
axonogenesis	1
neuron projection guidance	1
central nervous system development	1
animal organ development	1
head development	1
developmental process involved in reproduction	1
programmed cell death involved in cell development	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
developmental process	1
regulation of developmental process	1
cellular response to chemical stimulus	1
ganglion development	1
reproductive process	1
regulation of reproductive process	1
neuron migration	1
regulation of cell migration	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell migration	1
regulation of cell motility	1
cell surface receptor signaling pathway	1
transmembrane signaling receptor activity	1
netrin-activated signaling pathway	1
netrin receptor activity	1
cytoskeletal protein binding	1
kinase binding	1

Protein interactions and networks

STRING

1326 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UNC5C	NTN1	O95631	999
UNC5C	NTN3	O00634	786
UNC5C	NEO1	Q92859	776
UNC5C	NTN4	Q9HB63	736
UNC5C	SLIT3	O75094	679
UNC5C	PLD3	Q8IV08	667
UNC5C	ALOX12	P18054	649
UNC5C	AKAP9	Q99996	626
UNC5C	SLIT2	O94813	610
UNC5C	DCC	P43146	581
UNC5C	NTNG2	Q96CW9	568
UNC5C	NTNG1	Q9Y2I2	566
UNC5C	EPHB2	P29323	566
UNC5C	SEMA3E	O15041	544
UNC5C	NTN5	Q8WTR8	540

IntAct

13 interactions, top by confidence:

A	B	Type	Score
UNC5C	TUBB3	psi-mi:“MI:0915”(physical association)	0.520
UNC5C	NTN1	psi-mi:“MI:0915”(physical association)	0.400
M		psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
CACNA1C	IGLL5	psi-mi:“MI:0914”(association)	0.350
CACNA1C	CACNB4	psi-mi:“MI:0914”(association)	0.350
CACNA1C	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
TACSTD2	RIMOC1	psi-mi:“MI:0914”(association)	0.350
TMEM17	ESYT2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (41): UNC5C (Affinity Capture-MS), UNC5C (Affinity Capture-Western), UNC5C (Proximity Label-MS), UNC5C (Affinity Capture-RNA), UNC5C (Proximity Label-MS), UNC5C (Proximity Label-MS), UNC5C (Proximity Label-MS), UNC5C (Proximity Label-MS), UNC5C (Proximity Label-MS), UNC5C (Proximity Label-MS), UNC5C (Proximity Label-MS), UNC5C (Proximity Label-MS), UNC5C (Affinity Capture-RNA), UNC5C (Proximity Label-MS), UNC5C (Proximity Label-MS)

ESM2 similar proteins: A0A0G2JEB6, A0JM56, B0DOB4, B0FXQ5, B1ANS9, B4F7L9, B4GQJ7, B5DHW4, B7FF06, B7FF07, B7FF08, B7FF09, B7FF12, C5IAW9, F1LW30, F1P4W9, O08747, O95185, P0DM40, Q008S8, Q18264, Q32NR9, Q3V0B4, Q402B2, Q4G0P3, Q5R4M2, Q5T0N1, Q5XI14, Q6AXU1, Q6DCF6, Q6NRS1, Q6P2C0, Q6P5D8, Q6UXZ4, Q6ZTR5, Q6ZU64, Q761X5, Q7T2Z5, Q80W93, Q86YR7

Diamond homologs: A0A0G2K2P5, A0A8P0N4K0, C5IAW9, F1LW30, O08721, O08722, O08747, O62683, O95049, O95185, O97758, P39447, P57105, Q07157, Q0P5E6, Q13424, Q28626, Q32LE7, Q3T0C9, Q5EBL8, Q5ZIK2, Q61234, Q6NXB2, Q6QA76, Q6R653, Q6UXZ4, Q6ZN44, Q761X5, Q7KRY7, Q7T2Z5, Q80VW5, Q86UL8, Q8IV45, Q8IZJ1, Q8JGT4, Q8K1S2, Q8K1S3, Q8K1S4, Q95168, Q9CZG9

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
UNC5C	“down-regulates activity”	DCC	binding
NTN1	up-regulates	UNC5C	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

129 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	93
Likely benign	13
Benign	12

Top pathogenic / likely-pathogenic (0)

SpliceAI

4324 predictions. Top by Δscore:

Variant	Effect	Δscore
4:95169398:ACC:A	acceptor_loss	1.0000
4:95169399:CCTG:C	acceptor_loss	1.0000
4:95170150:CCA:C	donor_loss	1.0000
4:95170151:CA:C	donor_loss	1.0000
4:95170152:A:AT	donor_loss	1.0000
4:95170153:CCT:C	donor_loss	1.0000
4:95170330:TTCC:T	acceptor_loss	1.0000
4:95170331:TCCTG:T	acceptor_loss	1.0000
4:95170332:CC:C	acceptor_loss	1.0000
4:95170332:CCTG:C	acceptor_gain	1.0000
4:95170333:C:CC	acceptor_gain	1.0000
4:95170333:CTGTA:C	acceptor_loss	1.0000
4:95170334:T:G	acceptor_loss	1.0000
4:95170338:G:GC	acceptor_gain	1.0000
4:95170341:C:CT	acceptor_gain	1.0000
4:95170342:A:T	acceptor_gain	1.0000
4:95182892:CTTA:C	donor_loss	1.0000
4:95182893:TTA:T	donor_loss	1.0000
4:95182894:TACCT:T	donor_loss	1.0000
4:95182895:A:AC	donor_gain	1.0000
4:95182896:C:CC	donor_gain	1.0000
4:95182896:CCT:C	donor_gain	1.0000
4:95183060:TCC:T	acceptor_loss	1.0000
4:95183063:T:C	acceptor_loss	1.0000
4:95202726:CTTA:C	donor_loss	1.0000
4:95202727:TTACC:T	donor_loss	1.0000
4:95202728:TACC:T	donor_loss	1.0000
4:95202729:A:AC	donor_gain	1.0000
4:95202730:C:CA	donor_loss	1.0000
4:95202730:C:CT	donor_gain	1.0000

AlphaMissense

6082 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:95169352:A:G	L893P	1.000
4:95169385:A:G	F882S	1.000
4:95170175:G:T	A870D	1.000
4:95170186:C:A	W866C	1.000
4:95170186:C:G	W866C	1.000
4:95170188:A:G	W866R	1.000
4:95170188:A:T	W866R	1.000
4:95183006:A:G	F781S	1.000
4:95185076:A:G	W753R	1.000
4:95185076:A:T	W753R	1.000
4:95185111:A:G	L741P	1.000
4:95218986:A:G	L543P	1.000
4:95242562:C:A	W325C	1.000
4:95242562:C:G	W325C	1.000
4:95242580:C:A	W319C	1.000
4:95242580:C:G	W319C	1.000
4:95245023:A:C	C299W	1.000
4:95245024:C:G	C299S	1.000
4:95245024:C:T	C299Y	1.000
4:95245025:A:G	C299R	1.000
4:95245025:A:T	C299S	1.000
4:95245059:A:C	C287W	1.000
4:95245060:C:G	C287S	1.000
4:95245060:C:T	C287Y	1.000
4:95245061:A:G	C287R	1.000
4:95245061:A:T	C287S	1.000
4:95245065:C:A	R285S	1.000
4:95245065:C:G	R285S	1.000
4:95245066:C:A	R285M	1.000
4:95245066:C:G	R285T	1.000

dbSNP variants (sampled 300 via entrez): RS1000013222 (4:95461268 A>G), RS1000016193 (4:95405261 A>G), RS1000023589 (4:95183988 A>G), RS10000289 (4:95516455 T>A), RS1000032038 (4:95370177 A>G), RS1000043129 (4:95216960 T>C), RS1000043211 (4:95420221 AT>A), RS1000043743 (4:95433925 G>C), RS10000442 (4:95533055 A>C), RS1000048955 (4:95411981 A>T), RS1000059514 (4:95496618 T>C), RS1000059909 (4:95529897 T>C), RS1000061922 (4:95491472 A>G), RS1000062375 (4:95332051 C>A,G), RS1000075998 (4:95184184 T>C)

Disease associations

OMIM: gene MIM:603610 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST000655_2	Optic nerve measurement (cup-to-disc ratio)	4.000000e-06
GCST000825_5	Cerebrospinal P-tau181p levels	5.000000e-07
GCST001762_749	Obesity-related traits	5.000000e-06
GCST003434_3	Obsessive-compulsive symptoms	2.000000e-06
GCST004291_2	Residual cognition	3.000000e-06
GCST004862_217	Itch intensity from mosquito bite adjusted by bite size	9.000000e-07
GCST005195_113	Coronary artery disease	8.000000e-09
GCST005231_48	Major depressive disorder	5.000000e-06
GCST005440_11	Alcohol dependence symptom count	4.000000e-06
GCST006585_1864	Blood protein levels	2.000000e-11
GCST008114_28	Type 2 diabetes	5.000000e-06
GCST010538_11	Sum of carotid plaque area	1.000000e-06
GCST010539_1	Sum of stenosis	2.000000e-07
GCST010541_1	Maximum stenosis	1.000000e-06
GCST010570_3	Polycystic ovary syndrome (reproductive subtype)	1.000000e-08
GCST010988_220	Adult body size	7.000000e-09
GCST011365_126	Myocardial infarction	5.000000e-06

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004763	p-tau measurement
EFO:0003939	energy intake
EFO:0007802	obsessive-compulsive symptom measurement
EFO:0003925	cognition
EFO:0022597	aging
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0007835	alcohol dependence measurement
EFO:0006501	carotid plaque build

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases methylation, affects cotreatment	5
trichostatin A	affects cotreatment, increases expression	3
Panobinostat	increases expression, affects expression, increases reaction, affects cotreatment	3
bisphenol A	decreases methylation, increases expression	2
Benzo(a)pyrene	increases methylation, affects methylation	2
Aflatoxin B1	decreases methylation, increases methylation	2
aristolochic acid I	decreases expression	1
kojic acid	decreases expression	1
sodium arsenite	affects methylation	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	affects cotreatment, decreases methylation	1
7-(benzylamino)-1,3,4,8-tetrahydropyrrolo(4,3,2-de)quinolin-8(1H)-one	decreases expression	1
NSC 689534	affects binding, decreases expression	1
(+)-JQ1 compound	affects expression, increases reaction	1
Fulvestrant	affects cotreatment, decreases methylation	1
Vorinostat	affects cotreatment, increases expression	1
Carbamazepine	affects expression	1
Cisplatin	increases response to substance	1
Copper	affects binding, decreases expression	1
Diazinon	increases methylation	1
Diethylhexyl Phthalate	increases expression	1
Doxorubicin	decreases expression	1
Etoposide	increases response to substance	1
Lipopolysaccharides	increases expression, decreases reaction	1
Nickel	decreases expression	1
Oxygen	increases expression	1
Pesticides	decreases methylation	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.