GPRC5A

Summary

GPRC5A (G protein-coupled receptor class C group 5 member A, HGNC:9836) is a protein-coding gene on chromosome 12p13.1, encoding Retinoic acid-induced protein 3 (Q8NFJ5). Orphan receptor.

This gene encodes a member of the type 3 G protein-coupling receptor family, characterized by the signature 7-transmembrane domain motif. The encoded protein may be involved in interaction between retinoid acid and G protein signalling pathways. Retinoic acid plays a critical role in development, cellular growth, and differentiation. This gene may play a role in embryonic development and epithelial cell differentiation.

Source: NCBI Gene 9052 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 73 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_003979

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9836
Approved symbol	GPRC5A
Name	G protein-coupled receptor class C group 5 member A
Location	12p13.1
Locus type	gene with protein product
Status	Approved
Aliases	RAIG1, TIG1, PEIG-1
Ensembl gene	ENSG00000013588
Ensembl biotype	protein_coding
OMIM	604138
Entrez	9052

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 16 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000014914, ENST00000534831, ENST00000537783, ENST00000540125, ENST00000542056, ENST00000648791, ENST00000713574, ENST00000907830, ENST00000907831, ENST00000907832, ENST00000907833, ENST00000907834, ENST00000907835, ENST00000943568, ENST00000943569, ENST00000943570, ENST00000943571, ENST00000943572

RefSeq mRNA: 1 — MANE Select: NM_003979 NM_003979

CCDS: CCDS8657

Canonical transcript exons

ENST00000014914 — 4 exons

Exon	Start	End
ENSE00000822076	12908243	12909171
ENSE00003644115	12912084	12912142
ENSE00004020357	12891562	12891664
ENSE00004020358	12912447	12917937

Expression profiles

Bgee: expression breadth ubiquitous, 238 present calls, max score 98.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 64.9792 / max 2703.9757, expressed in 1220 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
124376	64.2554	1211
124377	0.2912	169
124378	0.2321	133
124379	0.2004	125

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
amniotic fluid	UBERON:0000173	98.99	gold quality
lower lobe of lung	UBERON:0008949	98.44	gold quality
endometrium epithelium	UBERON:0004811	98.28	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.13	gold quality
right lung	UBERON:0002167	98.01	gold quality
colonic mucosa	UBERON:0000317	97.84	gold quality
upper lobe of lung	UBERON:0008948	97.64	gold quality
upper lobe of left lung	UBERON:0008952	97.57	gold quality
mucosa of urinary bladder	UBERON:0001259	97.10	gold quality
visceral pleura	UBERON:0002401	97.00	gold quality
lung	UBERON:0002048	96.65	gold quality
cartilage tissue	UBERON:0002418	96.58	gold quality
esophagus squamous epithelium	UBERON:0006920	95.66	gold quality
rectum	UBERON:0001052	95.62	gold quality
ileal mucosa	UBERON:0000331	95.12	gold quality
periodontal ligament	UBERON:0008266	94.96	gold quality
epithelium of esophagus	UBERON:0001976	94.95	gold quality
palpebral conjunctiva	UBERON:0001812	94.13	gold quality
nasal cavity epithelium	UBERON:0005384	93.89	gold quality
squamous epithelium	UBERON:0006914	93.49	gold quality
left lobe of thyroid gland	UBERON:0001120	93.21	gold quality
thyroid gland	UBERON:0002046	92.91	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.76	gold quality
right lobe of thyroid gland	UBERON:0001119	92.45	gold quality
cervix squamous epithelium	UBERON:0006922	92.34	gold quality
renal glomerulus	UBERON:0000074	92.33	gold quality
metanephric glomerulus	UBERON:0004736	92.22	gold quality
pancreatic ductal cell	CL:0002079	92.20	silver quality
jejunal mucosa	UBERON:0000399	91.80	gold quality
tongue squamous epithelium	UBERON:0006919	91.32	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-GEOD-81383	yes	2115.39
E-ENAD-21	yes	1813.43
E-HCAD-15	yes	1585.91
E-MTAB-3929	yes	536.38
E-HCAD-24	yes	487.57
E-MTAB-10662	yes	363.45
E-CURD-114	yes	60.28
E-MTAB-8410	yes	45.58
E-HCAD-1	yes	27.57
E-GEOD-135922	yes	26.23
E-GEOD-130148	yes	11.12
E-MTAB-9689	no	265.20
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, JUN, RARA, RARG, RXRA, RXRB, SSRP1, TFAP2A, TP53

miRNA regulators (miRDB)

78 targeting GPRC5A, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-1255A	99.74	68.09	744
HSA-MIR-1255B-5P	99.74	68.16	741
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700

Literature-anchored findings (GeneRIF, showing 40)

• RAI3 is a cell growth-promoting gene and a novel P53 transcriptional target (PMID:15659406)
• This evidence explains one of the mechanisms of the GPRC5A-regulated cell growth in some cancer cell lines. (PMID:17055459)
• Gprc5a functions as a tumor suppressor in mouse lung, and human GPRC5A may share this property. (PMID:18000218)
• Mechanisms underlying the induction of the putative human tumor suppressor GPRC5A are reported. (PMID:19279407)
• analysis of RAI3 expression in normal and cancerous human breast tissue at both the mRNA and protein levels (PMID:19552806)
• Loss of GPRC5A is associated with lung adenocarcinomas. (PMID:20563252)
• Decreased GPRC5A expression is associated with non-small cell lung cancers and lung inflammation. (PMID:23154545)
• RAI3 may contribute to the malignant progression of hepatocellular carcinoma (PMID:23632812)
• Data indicate that in mammary tumors, the mRNA expression of GPRC5A significantly correlated with that of BRCA1. (PMID:24470238)
• The interaction of miR-103a-3p with each of the two 5’ UTR targets reduces the expression levels of both GPRC5A mRNA and GPRC5A protein in one normal epithelial and two pancreatic cancer cell lines. (PMID:24984703)
• EGFR interacted with GPRC5A and phosphorylated it in two conserved double-tyrosine motifs, Y317/Y320 and Y347/ Y350, at the C-terminal tail of GPRC5A. (PMID:25311788)
• Results show how GPRC5A deficiency leads to dysregulated EGFR and STAT3 signaling and lung tumorigenesis. (PMID:25744720)
• elevated levels of GPRC5A played significant roles in gastric cancer progression (PMID:26227221)
• under-expressed GPRC5A during lung tumorigenesis enhances any transcriptional stimulation through an active translational status. (PMID:27273304)
• Mutations of ARID1A, GPRC5A and MLL2 grant bladder cancer non-stem cells the capability of self-renewal. (PMID:27387124)
• GPRC5A is a potential oncogene in pancreatic ductal adenocarcinoma cells that is upregulated by gemcitabine with help from HuR. (PMID:27415424)
• our results implicate GPRC5A as a tumor suppressor in breast cancer cells, and GPRC5A exerts its tumor-suppressive function by inhibiting EGFR and its downstream pathway (PMID:27599526)
• findings reveal an unprecedented role for GPRC5A in regulation of the ITGB1-mediated cell adhesion and it’s downstream signaling, thus indicating a potential novel role for GPRC5A in human epithelial cancers. (PMID:27715394)
• Suppression of GPRC5a results in decreased cell growth, proliferation and migration in pancreatic cancer cell lines via a STAT3 modulated pathway, independent from ERK activation (PMID:28114355)
• Data show that G protein-coupled receptor, family C, group 5, member A protein (GPRC5A) regulates oxidative stress through vanin 1 protein (VNN1). (PMID:28316092)
• Study underscores genomic alterations that represent early events in the development of Kras mutant LUAD following Gprc5a loss and tobacco carcinogen exposure. (PMID:28653505)
• p53 overexpression and GPRC5A induction markedly inhibited tumor cell viability and induced apoptosis. (PMID:28849235)
• These results suggest RAI3 plays an important role in adipogenesis of hASCs and may have a potential use in the future application. (PMID:28870805)
• miR-204 inhibits cell proliferation in gastric cancer by targeting CKS1B, CXCL1 and GPRC5A. (PMID:29283424)
• On the basis of our findings in human DN and in Gprc5a deficient mice, we believe that chronic reduction in Gprc5a expression plays a pathogenic role in the progression of DN. Results in cell culture support our other findings in mice showing that Gprc5a modulates EGFR and TGF-b signaling in podocytes. (PMID:29636387)
• GPRC5a was upregulated in pancreatic cancer (PaCa) leading to an enhanced drug resistance in PaCa cells. (PMID:29949874)
• RAI3 overexpression is associated with poor prognosis in esophageal cancers (PMID:30707896)
• The lung tumor suppressor gene GPRC5A played a protective role in cigarette smoke-induced lung tumor initiation. (PMID:30901718)
• Our findings demonstrated that miR342 regulates the cell proliferation of glioma by targeting GPRC5A, which indicates that miR342 is a target of interest regarding the treatment of refractory glioma, and it may provide a promising prognostic and therapeutic strategy for glioma treatment. (PMID:31115523)
• RNA-seq revealed that GPRC5A KO PC3 cells had dysregulated expression of cell cycle-related genes, leading to cell cycle arrest at the G2/M phase. Furthermore, the registered gene expression profile data set showed that the expression level of GPRC5A in original lesions of prostate cancer patients with bone metastasis was higher than that without bone metastasis. (PMID:31276604)
• RAI3 knockdown enhances osteogenic differentiation of bone marrow mesenchymal stem cells via STAT3 signaling pathway. (PMID:32014253)
• Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer. (PMID:32115889)
• Identification of Sca-1(+)Abcg1(+) bronchioalveolar epithelial cells as the origin of lung adenocarcinoma in Gprc5a-knockout mouse model through the interaction between lung progenitor AT2 and Lgr5 cells. (PMID:32157214)
• GPRC5a suppresses the proliferation of non-small cell lung cancer under wild type p53 background. (PMID:32410473)
• RhoA/C inhibits proliferation by inducing the synthesis of GPRC5A. (PMID:32719397)
• GPRC5A reduction contributes to pollutant benzo[a]pyrene injury via aggravating murine fibrosis, leading to poor prognosis of IIP patients. (PMID:32758941)
• Prognostic and clinicopathological significance of GPRC5A in various cancers: A systematic review and meta-analysis. (PMID:33788883)
• Knockdown of GPRC5A inhibits cell proliferation, migration and invasion in osteosarcoma. (PMID:34350749)
• RAI3 expression is not associated with clinical outcomes of patients with non-small cell lung cancer. (PMID:36781501)
• The G protein-coupled receptor GPRC5A-a phorbol ester and retinoic acid-induced orphan receptor with roles in cancer, inflammation, and immunity. (PMID:37467514)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
		ENSDARG00000099947
mus_musculus	Gprc5a	ENSMUSG00000046733
rattus_norvegicus	Gprc5a	ENSRNOG00000008412

Paralogs (3): GPRC5D (ENSG00000111291), GPRC5B (ENSG00000167191), GPRC5C (ENSG00000170412)

Protein

Protein identifiers

Retinoic acid-induced protein 3 — Q8NFJ5 (reviewed: Q8NFJ5)

Alternative names: G-protein coupled receptor family C group 5 member A, Phorbol ester induced gene 1, Retinoic acid-induced gene 1 protein

All UniProt accessions (4): Q8NFJ5, A0A3B3ITN8, F5GWG3, H0YFN2

UniProt curated annotations — full annotation on UniProt →

Function. Orphan receptor. Could be involved in modulating differentiation and maintaining homeostasis of epithelial cells. This retinoic acid-inducible GPCR provide evidence for a possible interaction between retinoid and G-protein signaling pathways. Functions as a negative modulator of EGFR signaling. May act as a lung tumor suppressor.

Subunit / interactions. Interacts (via its transmembrane domain) with EGFR.

Subcellular location. Cell membrane. Cytoplasmic vesicle membrane.

Tissue specificity. Expressed at high level in fetal and adult lung tissues but repressed in most human lung cancers. Constitutively expressed in fetal kidney and adult placenta, kidney, prostate, testis, ovary, small intestine, colon, stomach, and spinal cord at low to moderate levels. Not detectable in fetal heart, brain, and liver and adult heart, brain, liver, skeletal muscle, pancreas, spleen, thymus, and peripheral leukocytes. According to PubMed:10783259, expressed at low but detectable level in pancreas and heart.

Post-translational modifications. Phosphorylated in two conserved double-tyrosine motifs, Tyr-317/Tyr-320 and Tyr-347/Tyr-350, by EGFR; leading to inactivation of the tumor suppressive function of GPRC5A in lung cancer cells. Tyr-317 and Tyr-320 are the preferred residues responsible for EGFR-mediated GPRC5A phosphorylation.

Induction. By all-trans retinoic acid (ATRA).

Similarity. Belongs to the G-protein coupled receptor 3 family.

RefSeq proteins (1): NP_003970* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR017978	GPCR_3_C	Domain
IPR051753	RA-inducible_GPCR3	Family

Pfam: PF00003

UniProt features (27 total): topological domain 8, transmembrane region 7, modified residue 6, sequence variant 3, chain 1, glycosylation site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NFJ5-F1	77.64	0.37

Functional residue map

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

Post-translational modifications (6): 301, 317, 320, 345, 347, 350

Glycosylation sites (1): 158

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 228 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, GOBP_REGULATION_OF_PROTEIN_TYROSINE_KINASE_ACTIVITY, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_NEGATIVE_REGULATION_OF_PEPTIDYL_TYROSINE_PHOSPHORYLATION, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_NEGATIVE_REGULATION_OF_KINASE_ACTIVITY, AMIT_EGF_RESPONSE_60_HELA, GOBP_NEGATIVE_REGULATION_OF_ERBB_SIGNALING_PATHWAY, MODULE_64, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_TYROSINE_KINASE_ACTIVITY, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, ONDER_CDH1_TARGETS_3_DN, GOMF_KINASE_ACTIVATOR_ACTIVITY

GO Biological Process (3): signal transduction (GO:0007165), negative regulation of epidermal growth factor-activated receptor activity (GO:0007175), G protein-coupled receptor signaling pathway (GO:0007186)

GO Molecular Function (4): G protein-coupled receptor activity (GO:0004930), protein kinase activator activity (GO:0030295), cadherin binding (GO:0045296), protein binding (GO:0005515)

GO Cellular Component (8): nucleolus (GO:0005730), plasma membrane (GO:0005886), cytoplasmic vesicle membrane (GO:0030659), vesicle (GO:0031982), signaling receptor complex (GO:0043235), extracellular exosome (GO:0070062), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
epidermal growth factor receptor activity	1
negative regulation of epidermal growth factor receptor signaling pathway	1
negative regulation of protein tyrosine kinase activity	1
negative regulation of signaling receptor activity	1
G protein-coupled receptor activity	1
signal transduction	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
protein kinase activity	1
kinase activator activity	1
protein kinase regulator activity	1
cell adhesion molecule binding	1
binding	1
nuclear lumen	1
intracellular membraneless organelle	1
membrane	1
cell periphery	1
vesicle membrane	1
cytoplasmic vesicle	1
membrane-bounded organelle	1
protein-containing complex	1
extracellular vesicle	1
cellular anatomical structure	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

776 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPRC5A	GRM2	Q14416	831
GPRC5A	GPR156	Q8NFN8	580
GPRC5A	GPR158	Q5T848	490
GPRC5A	APOLD1	Q96LR9	445
GPRC5A	KRTCAP3	Q53RY4	415
GPRC5A	VSIG8	P0DPA2	407
GPRC5A	TSPEAR	Q8WU66	406
GPRC5A	EIF4A1	P04765	403
GPRC5A	HSPA9	P30036	389
GPRC5A	GAS2	O43903	375
GPRC5A	PLCE1	Q9P212	362
GPRC5A	SNX8	Q9Y5X2	357
GPRC5A	GPR107	Q5VW38	341
GPRC5A	PLBD1	Q6P4A8	338
GPRC5A	PSMD1	Q99460	333

IntAct

102 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
KLRG2	GLRX3	psi-mi:“MI:0914”(association)	0.640
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640
CSGALNACT2	TPST1	psi-mi:“MI:0914”(association)	0.530
GPRC5B	STXBP3	psi-mi:“MI:0914”(association)	0.530
SLC34A2	LGALS8	psi-mi:“MI:0914”(association)	0.530
TMEM184A	SLC33A1	psi-mi:“MI:0914”(association)	0.530
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
RAMP2	GPRC5A	psi-mi:“MI:0915”(physical association)	0.470
GPRC5A	RAMP2	psi-mi:“MI:0915”(physical association)	0.470
RAMP2	GPRC5A	psi-mi:“MI:2364”(proximity)	0.470
GPRC5A	GAPDH	psi-mi:“MI:0915”(physical association)	0.400
Trim69		psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
RAMP1	GPRC5A	psi-mi:“MI:0915”(physical association)	0.400
RAMP3	GPRC5A	psi-mi:“MI:0915”(physical association)	0.400
GPRC5A	RAMP3	psi-mi:“MI:0915”(physical association)	0.400
MYH9	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Bmpr1a	PLEKHG3	psi-mi:“MI:0914”(association)	0.350

BioGRID (120): GPRC5A (Proximity Label-MS), GPRC5A (Affinity Capture-MS), GPRC5A (Affinity Capture-MS), GPRC5A (Affinity Capture-MS), GPRC5A (Affinity Capture-MS), GPRC5A (Affinity Capture-MS), GPRC5A (Affinity Capture-MS), GPRC5A (Affinity Capture-MS), GPRC5A (Affinity Capture-MS), GPRC5A (Affinity Capture-MS), GPRC5A (Affinity Capture-MS), GPRC5A (Affinity Capture-MS), GPRC5A (Affinity Capture-MS), GPRC5A (Affinity Capture-MS), GPRC5A (Affinity Capture-MS)

ESM2 similar proteins: A0A452G813, A0A8V0ZB02, A0JNI9, A2AWR3, B0UYF2, D3ZNF5, F4HWB6, G5ECB2, O01735, O35379, O80668, O94886, P32215, P34579, P41586, P70205, Q0DWA9, Q0WMJ8, Q19425, Q29627, Q3TWI9, Q4V3B8, Q53P98, Q56XP4, Q5F364, Q5PT55, Q5R826, Q5R9A7, Q5T3F8, Q5Z413, Q63633, Q7TN73, Q7Z3F1, Q8BXR1, Q8CBX0, Q8CG09, Q8GYS4, Q8HXI3, Q8K2P7, Q8NFJ5

Diamond homologs: Q2YDG0, Q3KRC4, Q8BHL4, Q8K3J9, Q8NFJ5, Q923Z0, Q9JIL6, Q9NQ84, Q9NZD1, Q9NZH0

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
hsa-miR-103a-3p	“down-regulates quantity by repression”	GPRC5A	“post transcriptional regulation”
EGFR	“down-regulates activity”	GPRC5A	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 130 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SLC transporter disorders	6	15.7×	5e-04
RHOQ GTPase cycle	6	13.9×	7e-04
Disorders of transmembrane transporters	7	12.5×	5e-04
ABC-family protein mediated transport	6	9.3×	4e-03
SLC-mediated transmembrane transport	9	6.8×	8e-04
Transport of small molecules	13	4.2×	1e-03
Neutrophil degranulation	12	3.5×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
amino acid transport	5	15.8×	5e-03
transport across blood-brain barrier	7	12.7×	1e-03
transmembrane transport	6	10.2×	5e-03
adenylate cyclase-activating G protein-coupled receptor signaling pathway	7	8.0×	5e-03
protein transport	10	4.4×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	56
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
815505	GRCh37/hg19 12p13.2-12.3(chr12:11737824-16780886)x1	Pathogenic

SpliceAI

915 predictions. Top by Δscore:

Variant	Effect	Δscore
12:12909168:CAAGG:C	donor_loss	1.0000
12:12909169:AAG:A	donor_loss	1.0000
12:12909170:AGGTA:A	donor_loss	1.0000
12:12909171:GG:G	donor_loss	1.0000
12:12909172:GTACA:G	donor_loss	1.0000
12:12909173:T:G	donor_loss	1.0000
12:12912078:TTTCA:T	acceptor_loss	1.0000
12:12912079:TTCA:T	acceptor_loss	1.0000
12:12912080:TCAGG:T	acceptor_loss	1.0000
12:12912081:CAGG:C	acceptor_loss	1.0000
12:12912082:A:T	acceptor_loss	1.0000
12:12912083:G:T	acceptor_loss	1.0000
12:12912139:GCAG:G	donor_gain	1.0000
12:12912143:GTA:G	donor_loss	1.0000
12:12912144:T:A	donor_loss	1.0000
12:12891663:GG:G	donor_gain	0.9900
12:12891664:GG:G	donor_gain	0.9900
12:12908240:CA:C	acceptor_loss	0.9900
12:12908241:A:AG	acceptor_gain	0.9900
12:12908241:AGGT:A	acceptor_loss	0.9900
12:12908242:G:GC	acceptor_loss	0.9900
12:12908242:G:GG	acceptor_gain	0.9900
12:12909159:G:GT	donor_gain	0.9900
12:12909160:A:T	donor_gain	0.9900
12:12912082:A:AG	acceptor_gain	0.9900
12:12912083:G:GG	acceptor_gain	0.9900
12:12912143:G:GG	donor_gain	0.9900
12:12912516:G:GT	donor_gain	0.9900
12:12912600:G:T	donor_gain	0.9900
12:12891660:CTAGG:C	donor_gain	0.9800

AlphaMissense

2338 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:12908673:A:C	S142R	0.989
12:12908675:C:A	S142R	0.989
12:12908675:C:G	S142R	0.989
12:12908502:T:C	F85L	0.987
12:12908504:C:A	F85L	0.987
12:12908504:C:G	F85L	0.987
12:12908778:T:C	F177L	0.982
12:12908780:T:A	F177L	0.982
12:12908780:T:G	F177L	0.982
12:12908550:T:C	F101L	0.981
12:12908552:T:A	F101L	0.981
12:12908552:T:G	F101L	0.981
12:12909009:T:A	W254R	0.981
12:12909009:T:C	W254R	0.981
12:12908562:T:C	F105L	0.979
12:12908564:T:A	F105L	0.979
12:12908564:T:G	F105L	0.979
12:12908985:A:C	S246R	0.979
12:12908987:C:A	S246R	0.979
12:12908987:C:G	S246R	0.979
12:12908484:T:C	F79L	0.975
12:12908486:T:A	F79L	0.975
12:12908486:T:G	F79L	0.975
12:12908330:G:C	W27C	0.970
12:12908330:G:T	W27C	0.970
12:12908541:T:C	F98L	0.970
12:12908543:C:A	F98L	0.970
12:12908543:C:G	F98L	0.970
12:12908345:A:C	E32D	0.967
12:12908345:A:T	E32D	0.967

dbSNP variants (sampled 300 via entrez): RS1000216664 (12:12900619 C>G,T), RS1000310242 (12:12899991 T>C), RS1000445540 (12:12894570 G>A), RS1000455434 (12:12894842 G>A), RS1000552260 (12:12899363 T>G), RS1000604497 (12:12899565 A>G), RS1000683386 (12:12899764 T>C), RS1000781971 (12:12895702 G>T), RS1000783533 (12:12905275 G>A,C), RS1000793430 (12:12895948 A>G), RS1000846110 (12:12906486 T>C), RS1000855250 (12:12917371 A>C,G), RS1000999379 (12:12890749 A>G), RS1001034025 (12:12916711 C>A), RS1001047882 (12:12900969 A>C,G)

Disease associations

OMIM: gene MIM:604138 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST003061_14	Cutaneous malignant melanoma	3.000000e-07
GCST004604_70	Hematocrit	1.000000e-09
GCST004615_75	Hemoglobin concentration	8.000000e-09
GCST007504_5	Nevus count	6.000000e-06
GCST007505_11	Nevus count or cutaneous melanoma	3.000000e-11
GCST007505_3	Nevus count or cutaneous melanoma	1.000000e-09
GCST010083_9	Hemoglobin levels	8.000000e-23
GCST90002383_48	Hematocrit	7.000000e-29
GCST90002384_302	Hemoglobin	3.000000e-27
GCST90002403_219	Red blood cell count	2.000000e-23

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004632	nevus count
EFO:0004305	erythrocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523896 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Class C Orphans

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, increases expression, decreases expression, decreases reaction, affects expression	6
Cyclosporine	decreases expression, increases expression	5
sodium arsenite	decreases expression	3
Ethinyl Estradiol	decreases expression, affects expression	3
Tobacco Smoke Pollution	increases expression, affects expression	3
Tretinoin	increases expression	3
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression	3
bisphenol A	affects expression, decreases expression	2
cadmium sulfate	increases expression	2
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Resveratrol	affects cotreatment, decreases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Hydrogen Peroxide	affects expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	decreases reaction, decreases expression	2
Valproic Acid	increases methylation, increases expression	2
Genistein	affects expression, decreases expression	2
3,19-(2-bromobenzylidene)andrographolide	increases expression, decreases response to substance	1
methyleugenol	increases expression	1
propionaldehyde	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
lead acetate	increases expression	1
senecionine	increases expression	1
senkirkine	increases expression	1
heliotrine	increases expression	1
salinomycin	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4883476	Binding	PRESTO-Tango GPCRome screening (GPRC5A)	Data for DCP probe UCSF924

Clinical trials (associated diseases)

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