GPRC5D

Summary

GPRC5D (G protein-coupled receptor class C group 5 member D, HGNC:13310) is a protein-coding gene on chromosome 12p13.1, encoding G-protein coupled receptor family C group 5 member D (Q9NZD1). G-protein coupled receptor involved in hard keratin expression and likely plays a role in the development of hair and nails.

The protein encoded by this gene is a member of the G protein-coupled receptor family; however, the specific function of this gene has not yet been determined.

Source: NCBI Gene 55507 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 45 total
• Druggable target: yes
• MANE Select transcript: NM_018654

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13310
Approved symbol	GPRC5D
Name	G protein-coupled receptor class C group 5 member D
Location	12p13.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000111291
Ensembl biotype	protein_coding
OMIM	607437
Entrez	55507

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000228887, ENST00000396333

RefSeq mRNA: 1 — MANE Select: NM_018654 NM_018654

CCDS: CCDS8658

Canonical transcript exons

ENST00000228887 — 4 exons

Exon	Start	End
ENSE00000721894	12949490	12950429
ENSE00000822078	12942261	12942328
ENSE00003963254	12940575	12940849
ENSE00003963354	12952107	12952170

Expression profiles

Bgee: expression breadth ubiquitous, 155 present calls, max score 83.01.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1175 / max 52.3835, expressed in 24 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129772	0.1047	23
129773	0.0128	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.01	silver quality
pancreatic ductal cell	CL:0002079	77.12	silver quality
upper lobe of left lung	UBERON:0008952	74.76	gold quality
tibialis anterior	UBERON:0001385	73.98	silver quality
diaphragm	UBERON:0001103	73.89	gold quality
hair follicle	UBERON:0002073	73.69	gold quality
upper lobe of lung	UBERON:0008948	72.03	gold quality
mucosa of transverse colon	UBERON:0004991	71.79	gold quality
rectum	UBERON:0001052	70.91	gold quality
right lung	UBERON:0002167	70.88	gold quality
minor salivary gland	UBERON:0001830	69.89	gold quality
olfactory bulb	UBERON:0002264	67.98	gold quality
type B pancreatic cell	CL:0000169	67.72	gold quality
bone marrow cell	CL:0002092	66.72	gold quality
mouth mucosa	UBERON:0003729	66.07	gold quality
esophagus mucosa	UBERON:0002469	65.99	gold quality
ileal mucosa	UBERON:0000331	65.97	silver quality
saliva-secreting gland	UBERON:0001044	65.94	gold quality
islet of Langerhans	UBERON:0000006	64.73	gold quality
lower esophagus mucosa	UBERON:0035834	64.12	gold quality
skin of abdomen	UBERON:0001416	62.78	gold quality
right lobe of liver	UBERON:0001114	62.60	gold quality
skin of leg	UBERON:0001511	62.52	gold quality
left lobe of thyroid gland	UBERON:0001120	61.93	gold quality
right atrium auricular region	UBERON:0006631	61.72	gold quality
colonic epithelium	UBERON:0000397	61.56	gold quality
lung	UBERON:0002048	61.56	gold quality
thyroid gland	UBERON:0002046	61.09	gold quality
endothelial cell	CL:0000115	61.01	gold quality
zone of skin	UBERON:0000014	60.87	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.15
E-CURD-10	no	81.73

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 6)

• Overexpression of G protein-coupled receptor 5D in the bone marrow is associated with poor prognosis in patients with multiple myeloma. (PMID:22591013)
• GPRC5D in MM cells makes this gene and its encoded surface protein as promising markers for monitoring the tumor load and hopefully also as targets for antimyeloma antibodies. (PMID:23510526)
• GPRC5D as a promising therapeutic target in EGFR-wild and immuno-cold non-small cell lung cancer. (PMID:37574551)
• Acquired resistance to a GPRC5D-directed T-cell engager in multiple myeloma is mediated by genetic or epigenetic target inactivation. (PMID:37653140)
• Genetic Basis of Relapse after GPRC5D-Targeted CAR T Cells. (PMID:37819961)
• GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review. (PMID:38307865)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
		ENSDARG00000099947
mus_musculus	Gprc5d	ENSMUSG00000030205
rattus_norvegicus	Gprc5d	ENSRNOG00000008439

Paralogs (3): GPRC5A (ENSG00000013588), GPRC5B (ENSG00000167191), GPRC5C (ENSG00000170412)

Protein

Protein identifiers

G-protein coupled receptor family C group 5 member D — Q9NZD1 (reviewed: Q9NZD1)

All UniProt accessions (1): Q9NZD1

UniProt curated annotations — full annotation on UniProt →

Function. G-protein coupled receptor involved in hard keratin expression and likely plays a role in the development of hair and nails.

Subunit / interactions. Homodimer.

Subcellular location. Cell membrane.

Tissue specificity. Widely expressed in the peripheral system. Expression pattern is high in pancreas, medium in kidney, small intestine, spleen and testis, low in lung, colon, leukocyte, prostate and thymus and not detectable in brain, heart, liver, placenta, skeletal muscle and ovary.

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NZD1-1	1	yes
Q9NZD1-2	2
Q9NZD1-3	3

RefSeq proteins (1): NP_061124* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR017978	GPCR_3_C	Domain
IPR051753	RA-inducible_GPCR3	Family

Pfam: PF00003

UniProt features (40 total): helix 12, topological domain 8, transmembrane region 7, turn 5, splice variant 3, strand 3, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9IMA	ELECTRON MICROSCOPY	2.65
8YZK	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZD1-F1	76.43	0.44

Antibody-complex structures (SAbDab): 2 — 8YZK, 9IMA

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 70 (showing top): NKX25_02, AAAYRNCTG_UNKNOWN, GOMF_KINASE_ACTIVATOR_ACTIVITY, MARTINEZ_RB1_TARGETS_DN, TATA_C, AACTTT_UNKNOWN, GFI1_01, MODULE_207, MODULE_342, ZHAN_MULTIPLE_MYELOMA_CD2_DN, GOCC_RECEPTOR_COMPLEX, GOMF_ENZYME_ACTIVATOR_ACTIVITY, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY, SMAD_Q6

GO Biological Process (2): signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186)

GO Molecular Function (3): G protein-coupled receptor activity (GO:0004930), protein kinase activator activity (GO:0030295), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), signaling receptor complex (GO:0043235), extracellular exosome (GO:0070062), membrane (GO:0016020)

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
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
binding	1
membrane	1
cell periphery	1
protein-containing complex	1
extracellular vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

414 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPRC5D	FCRL5	Q96RD9	819
GPRC5D	CEP70	Q8NHQ1	705
GPRC5D	SLAMF7	Q9NQ25	696
GPRC5D	TNFRSF17	Q02223	571
GPRC5D	CD38	P28907	554
GPRC5D	SDC1	P18827	522
GPRC5D	CCL4	P13236	477
GPRC5D	GPR156	Q8NFN8	476
GPRC5D	TNFRSF13B	O14836	446
GPRC5D	CD19	P15391	440
GPRC5D	KRTAP4-16	G5E9R7	399
GPRC5D	LY9	Q9HBG7	398
GPRC5D	ITGB7	P26010	370
GPRC5D	TNFRSF9	Q07011	370
GPRC5D	CRBN	Q96SW2	357

IntAct

98 interactions, top by confidence:

A	B	Type	Score
BTN2A2	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
TWSG1	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
TMEM19	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
OSMR	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
SYNDIG1	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
FXYD3	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
NRAC	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
LHFPL5	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
LRRC25	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
PVR	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
MS4A6A	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
UNC93B1	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
SLC66A1	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
TMEM79	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
SLC30A2	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
IFITM3	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
PMP22	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
TMEM208	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
EMP1	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
CCL4	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
GPRC5D	YIPF1	psi-mi:“MI:0915”(physical association)	0.560
TUSC5	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (72): SEC63 (Affinity Capture-MS), VPS45 (Affinity Capture-MS), GPRC5D (Two-hybrid), GPRC5D (Two-hybrid), GPRC5D (Two-hybrid), GPRC5D (Two-hybrid), GPRC5D (Two-hybrid), GPRC5D (Two-hybrid), GPRC5D (Two-hybrid), GPRC5D (Two-hybrid), GPRC5D (Two-hybrid), GPRC5D (Two-hybrid), IGFBP5 (Two-hybrid), BTN2A2 (Two-hybrid), APOL3 (Two-hybrid)

ESM2 similar proteins: A0A1B0GTI8, A0A2Z2U4G9, A0A494BA31, A5D6W6, A6NC51, A6NDP7, A6NFC5, A6NH21, A6NJY4, A8WCG0, B0BNG2, B1AQL3, E9Q9H8, O43246, P43219, P48546, Q1HG43, Q1HG44, Q2KIG8, Q32L10, Q497B3, Q49LS0, Q49LS7, Q4VV71, Q53RY4, Q58CW5, Q5REM8, Q5XK03, Q658P3, Q6PEY1, Q6UW68, Q80SU6, Q8C0T0, Q8K177, Q8K4R8, Q8K4V2, Q8N130, Q8VE49, Q91XE8, Q923Z0

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

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 32 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.

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein transport	5	12.5×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	40
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

365 predictions. Top by Δscore:

Variant	Effect	Δscore
12:12942329:C:CC	acceptor_gain	0.9800
12:12949489:CCT:C	donor_gain	0.9800
12:12949485:TGTAC:T	donor_loss	0.9600
12:12949486:GTAC:G	donor_loss	0.9600
12:12949487:TAC:T	donor_loss	0.9600
12:12949488:ACCT:A	donor_loss	0.9600
12:12949489:C:T	donor_loss	0.9600
12:12949501:T:TA	donor_gain	0.9500
12:12949554:G:A	donor_gain	0.9500
12:12940846:CAGT:C	acceptor_gain	0.9400
12:12949662:G:GT	donor_gain	0.9400
12:12942328:GCT:G	acceptor_loss	0.9200
12:12942329:C:G	acceptor_loss	0.9200
12:12942330:T:G	acceptor_loss	0.9200
12:12942331:G:C	acceptor_loss	0.9200
12:12942337:C:CT	acceptor_gain	0.9200
12:12949491:T:TA	donor_gain	0.9100
12:12940850:C:CC	acceptor_gain	0.9000
12:12942337:C:T	acceptor_gain	0.9000
12:12942338:A:T	acceptor_gain	0.8800
12:12942325:CGGG:C	acceptor_gain	0.8700
12:12949490:C:G	donor_loss	0.8700
12:12942333:A:C	acceptor_loss	0.8600
12:12948077:GCTAC:G	acceptor_gain	0.8600
12:12949460:C:A	donor_gain	0.8500
12:12949483:AATGT:A	donor_loss	0.8500
12:12949484:ATGTA:A	donor_loss	0.8500
12:12942332:AAA:A	acceptor_loss	0.8400
12:12949420:A:AC	donor_gain	0.8300
12:12949421:C:CC	donor_gain	0.8300

AlphaMissense

2250 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:12949974:A:C	S137R	0.991
12:12949974:A:T	S137R	0.991
12:12949976:T:G	S137R	0.991
12:12949634:A:G	W251R	0.987
12:12949634:A:T	W251R	0.987
12:12950145:G:C	F80L	0.983
12:12950145:G:T	F80L	0.983
12:12950147:A:G	F80L	0.983
12:12949727:A:G	W220R	0.981
12:12949727:A:T	W220R	0.981
12:12949736:A:G	W217R	0.981
12:12949736:A:T	W217R	0.981
12:12949638:G:C	N249K	0.979
12:12949638:G:T	N249K	0.979
12:12950097:A:C	F96L	0.979
12:12950097:A:T	F96L	0.979
12:12950099:A:G	F96L	0.979
12:12950178:A:C	S69R	0.977
12:12950178:A:T	S69R	0.977
12:12950180:T:G	S69R	0.977
12:12950288:C:G	G33R	0.977
12:12949875:A:C	F170L	0.975
12:12949875:A:T	F170L	0.975
12:12949877:A:G	F170L	0.975
12:12950085:A:C	F100L	0.975
12:12950085:A:T	F100L	0.975
12:12950087:A:G	F100L	0.975
12:12950069:A:G	C106R	0.973
12:12950171:C:G	G72R	0.969
12:12950171:C:T	G72R	0.969

dbSNP variants (sampled 300 via entrez): RS1000064075 (12:12943032 C>T), RS1000168465 (12:12948551 T>A), RS1000399523 (12:12947958 G>T), RS1000505118 (12:12947299 A>C,G), RS1000682054 (12:12941679 C>T), RS1000766562 (12:12947001 A>G), RS1001112749 (12:12953733 C>G), RS1002183999 (12:12945338 G>A), RS1002353852 (12:12941906 C>T), RS1002422869 (12:12945028 G>A), RS1002430123 (12:12953081 C>A), RS1002756632 (12:12943533 C>G), RS1002804564 (12:12944386 C>A), RS1002856866 (12:12944604 G>A), RS1003186866 (12:12946123 A>G)

Disease associations

OMIM: gene MIM:607437 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523925 (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

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
bisphenol A	affects cotreatment, increases expression	1
afimoxifene	affects response to substance	1
Arsenic Trioxide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arbutin	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	increases expression	1
Zinc	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Particulate Matter	decreases expression, increases abundance	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
CHEMBL4883479	Binding	PRESTO-Tango GPCRome screening (GPRC5D)	Data for DCP probe UCSF924

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 1 spontaneously immortalized cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E6QM	Genomeditech CHO-K1 H_GPRC5D	Spontaneously immortalized cell line	Female
CVCL_E6U1	Genomeditech HEK-293 H_GPRC5D	Transformed cell line	Female
CVCL_E6WJ	Genomeditech MC-38 H_GPRC5D	Cancer cell line	Female
CVCL_E8JB	BxPC-3 human GPRC5D-HA	Cancer cell line	Female
CVCL_E8JD	BxPC-3 human GPRC5D	Cancer cell line	Female

Clinical trials (associated diseases)

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