GPR176

Summary

GPR176 (G protein-coupled receptor 176, HGNC:32370) is a protein-coding gene on chromosome 15q14-q15.1, encoding G-protein coupled receptor 176 (Q14439). Orphan receptor involved in normal circadian rhythm behavior.

Members of the G protein-coupled receptor family, such as GPR176, are cell surface receptors involved in responses to hormones, growth factors, and neurotransmitters (Hata et al., 1995 [PubMed 7893747]).

Source: NCBI Gene 11245 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 84 total
• Druggable target: yes
• MANE Select transcript: NM_007223

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:32370
Approved symbol	GPR176
Name	G protein-coupled receptor 176
Location	15q14-q15.1
Locus type	gene with protein product
Status	Approved
Aliases	Gm1012
Ensembl gene	ENSG00000166073
Ensembl biotype	protein_coding
OMIM	612183
Entrez	11245

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000299092, ENST00000543580, ENST00000558041, ENST00000560729, ENST00000561100

RefSeq mRNA: 3 — MANE Select: NM_007223 NM_001271854, NM_001271855, NM_007223

CCDS: CCDS10051, CCDS61588, CCDS61589

Canonical transcript exons

ENST00000561100 — 3 exons

Exon	Start	End
ENSE00001276764	39919855	39920266
ENSE00002559401	39799008	39802254
ENSE00003809755	39807006	39807258

Expression profiles

Bgee: expression breadth ubiquitous, 224 present calls, max score 94.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.1974 / max 133.4417, expressed in 1377 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149459	5.0264	888
149461	4.7712	1082
149460	3.9517	924
149464	1.1322	644
149463	0.9847	448
149462	0.3313	147

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	94.10	gold quality
ascending aorta	UBERON:0001496	90.97	gold quality
thoracic aorta	UBERON:0001515	90.76	gold quality
saphenous vein	UBERON:0007318	89.79	gold quality
right coronary artery	UBERON:0001625	89.07	gold quality
aorta	UBERON:0000947	88.02	gold quality
descending thoracic aorta	UBERON:0002345	87.57	gold quality
pons	UBERON:0000988	87.21	gold quality
cerebellar hemisphere	UBERON:0002245	86.75	gold quality
cerebellar cortex	UBERON:0002129	86.69	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.21	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.20	gold quality
popliteal artery	UBERON:0002250	85.99	gold quality
tibial artery	UBERON:0007610	85.99	gold quality
cerebellum	UBERON:0002037	85.51	gold quality
sperm	CL:0000019	85.33	gold quality
nucleus accumbens	UBERON:0001882	85.24	gold quality
coronary artery	UBERON:0001621	85.16	gold quality
left coronary artery	UBERON:0001626	85.14	gold quality
right frontal lobe	UBERON:0002810	83.39	gold quality
cingulate cortex	UBERON:0003027	82.80	gold quality
prefrontal cortex	UBERON:0000451	82.78	gold quality
anterior cingulate cortex	UBERON:0009835	82.65	gold quality
male germ cell	CL:0000015	82.34	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.37	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	81.08	gold quality
superior vestibular nucleus	UBERON:0007227	81.04	gold quality
substantia nigra pars compacta	UBERON:0001965	80.90	silver quality
frontal cortex	UBERON:0001870	80.86	gold quality
neocortex	UBERON:0001950	80.80	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-109979	yes	212.08
E-MTAB-6819	no	154.09
E-ANND-3	no	3.61

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

88 targeting GPR176, 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-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-3685	99.62	68.83	1621
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-4649-3P	99.56	66.90	1783

Literature-anchored findings (GeneRIF, showing 6)

• Data suggest that Gpr176 is an SCN-(suprachiasmatic nucleus-)enriched orphan GPCR (G-protein-coupled receptor) that sets the pace of circadian behavior. [REVIEW] (PMID:28502923)
• GPR176 Promotes Cancer Progression by Interacting with G Protein GNAS to Restrain Cell Mitophagy in Colorectal Cancer. (PMID:36905238)
• High expression of GPR176 predicts poor prognosis of gastric cancer patients and promotes the proliferation, migration, and invasion of gastric cancer cells. (PMID:37291181)
• The promoting effects of GPR176 expression on proliferation, chemoresistance, lipogenesis and invasion of oesophageal cancer. (PMID:37584712)
• The oncogenic roles of GPR176 in ovarian cancer: a molecular target for aggressiveness and gene therapy. (PMID:38835234)
• GPR176 promotes fibroblast-to-myofibroblast transition in organ fibrosis progression. (PMID:39047914)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gpr176	ENSDARG00000042515
mus_musculus	Gpr176	ENSMUSG00000040133
rattus_norvegicus	Gpr176	ENSRNOG00000005971

Paralogs (3): GPR61 (ENSG00000156097), GPR62 (ENSG00000180929), GPR135 (ENSG00000181619)

Protein

Protein identifiers

G-protein coupled receptor 176 — Q14439 (reviewed: Q14439)

Alternative names: HB-954

All UniProt accessions (1): Q14439

UniProt curated annotations — full annotation on UniProt →

Function. Orphan receptor involved in normal circadian rhythm behavior. Acts through the G-protein subclass G(z)-alpha and has an agonist-independent basal activity to repress cAMP production.

Subcellular location. Cell membrane.

Similarity. Belongs to the G-protein coupled receptor 1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q14439-1	1	yes
Q14439-2	2
Q14439-3	3

RefSeq proteins (3): NP_001258783, NP_001258784, NP_009154* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR043523	GPCR_176_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (24 total): topological domain 8, transmembrane region 7, glycosylation site 4, splice variant 2, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14439-F1	66.71	0.19

Functional residue map

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

Glycosylation sites (4): 4, 11, 17, 27

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-418555	G alpha (s) signalling events

MSigDB gene sets: 112 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_CIRCADIAN_RHYTHM, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_BEHAVIOR, GOBP_CELL_CELL_SIGNALING, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, MODULE_120, DACOSTA_UV_RESPONSE_VIA_ERCC3_TTD_DN, GOBP_SYNAPTIC_SIGNALING, BROWNE_HCMV_INFECTION_24HR_DN, MORF_EPHA7, MORF_RAB3A, GOBP_RHYTHMIC_BEHAVIOR, GOBP_ADENYLATE_CYCLASE_INHIBITING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, MODULE_175

GO Biological Process (8): G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), chemical synaptic transmission (GO:0007268), circadian behavior (GO:0048512), cell communication (GO:0007154), signal transduction (GO:0007165), signaling (GO:0023052), rhythmic process (GO:0048511)

GO Molecular Function (1): G protein-coupled receptor activity (GO:0004930)

GO Cellular Component (3): plasma membrane (GO:0005886), synapse (GO:0045202), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
G protein-coupled receptor activity	1
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase inhibitor activity	1
anterograde trans-synaptic signaling	1
rhythmic behavior	1
circadian rhythm	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
regulation of biological process	1
biological_process	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
membrane	1
cell periphery	1
cell junction	1
cellular anatomical structure	1

Protein interactions and networks

STRING

568 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPR176	GPR17	Q13304	619
GPR176	GPR153	Q6NV75	570
GPR176	GPR75	O95800	565
GPR176	VSTM5	A8MXK1	546
GPR176	GNAZ	P19086	540
GPR176	GPR150	Q8NGU9	516
GPR176	GPR149	Q86SP6	492
GPR176	GPR22	Q99680	483
GPR176	GPR151	Q8TDV0	479
GPR176	GPR85	P60893	478
GPR176	GNAT2	P19087	458
GPR176	GPR161	Q8N6U8	452
GPR176	GPR183	P32249	447
GPR176	MAS1	P04201	441
GPR176	GPR27	Q9NS67	440

IntAct

7 interactions, top by confidence:

A	B	Type	Score
	ESYT2	psi-mi:“MI:0914”(association)	0.350
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
CXCR4	ESYT2	psi-mi:“MI:0914”(association)	0.350
EDEM2	HIGD1C	psi-mi:“MI:0914”(association)	0.350
GPR17	C1QTNF9B	psi-mi:“MI:0914”(association)	0.350
TMEM169	PTGES3L-AARSD1	psi-mi:“MI:0914”(association)	0.350

BioGRID (4): GPR176 (Affinity Capture-MS), GPR176 (Proximity Label-MS), GPR176 (Proximity Label-MS), GPR176 (Affinity Capture-MS)

ESM2 similar proteins: A2BGS3, A6NGA9, E7F594, O36364, O60478, O60883, O95800, O95838, P03208, P16849, P31389, P34590, P35367, P49219, Q03613, Q09351, Q09964, Q09965, Q14439, Q16950, Q16951, Q2KI97, Q3U3F9, Q5FVG1, Q5IXF8, Q5UAW9, Q60755, Q64017, Q66615, Q66H29, Q6P7G9, Q6SW98, Q6X632, Q7TSN5, Q7TSN6, Q80W35, Q80WT4, Q8BNQ3, Q8C206, Q8CIM5

Diamond homologs: A1ZAX0, B2ZI34, O18982, O42179, O54798, O54799, O62709, O62809, O77621, O97663, O97967, P21450, P21451, P21729, P24053, P24530, P25095, P25101, P26684, P28088, P28336, P29089, P29754, P30550, P30731, P30974, P31391, P32247, P33535, P34976, P35370, P35371, P35372, P35377, P35463, P41146, P42866, P47211, P47748, P47751

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	75
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2408 predictions. Top by Δscore:

Variant	Effect	Δscore
15:39802252:TAC:T	acceptor_gain	1.0000
15:39807269:A:C	acceptor_gain	1.0000
15:39919850:CTTAC:C	donor_loss	1.0000
15:39919851:TTA:T	donor_loss	1.0000
15:39919852:TACC:T	donor_loss	1.0000
15:39919853:A:AC	donor_gain	1.0000
15:39919854:C:CC	donor_gain	1.0000
15:39919854:C:CG	donor_loss	1.0000
15:39919854:CCGAG:C	donor_gain	1.0000
15:39802250:AGTAC:A	acceptor_gain	0.9900
15:39802251:GTAC:G	acceptor_gain	0.9900
15:39802253:AC:A	acceptor_gain	0.9900
15:39802253:ACC:A	acceptor_loss	0.9900
15:39802254:CC:C	acceptor_gain	0.9900
15:39802255:C:CC	acceptor_gain	0.9900
15:39802255:C:CG	acceptor_loss	0.9900
15:39802262:A:AC	acceptor_gain	0.9900
15:39802262:A:C	acceptor_gain	0.9900
15:39802265:C:CT	acceptor_gain	0.9900
15:39805295:C:CT	acceptor_gain	0.9900
15:39805296:A:T	acceptor_gain	0.9900
15:39805409:T:C	acceptor_gain	0.9900
15:39806999:ATCTT:A	donor_loss	0.9900
15:39807001:CTTA:C	donor_loss	0.9900
15:39807002:TTA:T	donor_loss	0.9900
15:39807003:T:TA	donor_loss	0.9900
15:39807004:A:AA	donor_loss	0.9900
15:39807074:G:GT	donor_gain	0.9900
15:39807269:A:AC	acceptor_gain	0.9900
15:39807570:AAT:A	donor_gain	0.9900

AlphaMissense

3361 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:39807029:G:C	S134R	0.999
15:39807029:G:T	S134R	0.999
15:39807031:T:G	S134R	0.999
15:39801223:A:G	L486P	0.998
15:39802158:A:C	S174R	0.998
15:39802158:A:T	S174R	0.998
15:39802160:T:G	S174R	0.998
15:39802181:A:G	W167R	0.997
15:39802181:A:T	W167R	0.997
15:39807006:C:A	R142M	0.997
15:39807015:G:T	A139D	0.997
15:39807185:G:C	N82K	0.997
15:39807185:G:T	N82K	0.997
15:39801843:G:C	S279R	0.996
15:39801843:G:T	S279R	0.996
15:39801845:T:G	S279R	0.996
15:39801946:A:G	L245P	0.996
15:39801946:A:T	L245H	0.996
15:39802030:G:C	P217R	0.995
15:39802253:A:C	Y143D	0.995
15:39802254:C:A	R142S	0.995
15:39802254:C:G	R142S	0.995
15:39807006:C:G	R142T	0.995
15:39807183:A:G	L83P	0.995
15:39807195:A:G	F79S	0.995
15:39801290:A:G	W464R	0.994
15:39801290:A:T	W464R	0.994
15:39801761:A:G	W307R	0.994
15:39801761:A:T	W307R	0.994
15:39802171:G:T	A170E	0.994

dbSNP variants (sampled 300 via entrez): RS1000032131 (15:39854236 T>C,G), RS1000034208 (15:39833071 G>A), RS1000062793 (15:39818238 T>C), RS1000068515 (15:39876167 G>T), RS1000114345 (15:39807531 A>C), RS1000139625 (15:39894996 A>G), RS1000149875 (15:39852152 T>C), RS1000189698 (15:39921332 T>C), RS1000208326 (15:39859233 G>C,T), RS1000259190 (15:39858922 T>C), RS1000279684 (15:39848317 T>C), RS1000300004 (15:39842180 C>A,G), RS1000336368 (15:39799064 T>C), RS1000414705 (15:39865122 C>A), RS1000440179 (15:39841801 A>G)

Disease associations

OMIM: gene MIM:612183 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007005_7	Logical memory (immediate recall) in normal cognition	5.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004874	memory performance

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523869 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Class A Orphans with no pharmacology

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation	2
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
Benzo(a)pyrene	decreases methylation, increases expression, increases methylation	2
Estradiol	increases expression, affects expression, affects cotreatment, affects reaction	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Valproic Acid	increases expression	2
methylmercuric chloride	decreases expression	1
manganese chloride	increases expression, affects cotreatment, increases abundance	1
potassium chromate(VI)	decreases expression	1
aflatoxin B2	increases methylation	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression, affects cotreatment	1
Vorinostat	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Catechin	affects cotreatment, increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Doxorubicin	affects response to substance	1
Manganese	increases expression, affects cotreatment, increases abundance	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	decreases expression	1
Vinblastine	affects response to substance	1
Aflatoxin B1	decreases methylation	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4883433	Binding	PRESTO-Tango GPCRome screening (GPR176)	Data for DCP probe UCSF924

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_KX48	PathHunter CHO-K1 GPR176 beta-arrestin	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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