GPR65

Summary

GPR65 (G protein-coupled receptor 65, HGNC:4517) is a protein-coding gene on chromosome 14q31.3, encoding G-protein coupled receptor 65 (Q8IYL9). Proton-sensing G-protein coupled receptor activated by extracellular pH, which is required to monitor pH changes and generate adaptive reactions.

Enables G protein-coupled receptor activity. Involved in several processes, including activation of GTPase activity; positive regulation of stress fiber assembly; and response to acidic pH. Located in plasma membrane.

Source: NCBI Gene 8477 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 37 total
• Druggable target: yes — 11 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003608

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4517
Approved symbol	GPR65
Name	G protein-coupled receptor 65
Location	14q31.3
Locus type	gene with protein product
Status	Approved
Aliases	hTDAG8, TDAG8
Ensembl gene	ENSG00000140030
Ensembl biotype	protein_coding
OMIM	604620
Entrez	8477

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000267549, ENST00000905165

RefSeq mRNA: 1 — MANE Select: NM_003608 NM_003608

CCDS: CCDS9879

Canonical transcript exons

ENST00000267549 — 2 exons

Exon	Start	End
ENSE00000941113	88010389	88014811
ENSE00001300866	88005135	88005222

Expression profiles

Bgee: expression breadth ubiquitous, 180 present calls, max score 90.06.

FANTOM5 (CAGE): breadth broad, TPM avg 20.5997 / max 2666.8251, expressed in 569 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
140945	16.7133	556
140946	3.1995	354
140947	0.6023	169
140949	0.0478	24
140948	0.0367	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
leukocyte	CL:0000738	90.06	gold quality
mononuclear cell	CL:0000842	89.91	gold quality
monocyte	CL:0000576	89.79	gold quality
periodontal ligament	UBERON:0008266	89.51	gold quality
granulocyte	CL:0000094	89.06	gold quality
blood	UBERON:0000178	85.21	gold quality
bone marrow	UBERON:0002371	83.03	gold quality
vermiform appendix	UBERON:0001154	80.25	gold quality
trabecular bone tissue	UBERON:0002483	78.69	gold quality
spleen	UBERON:0002106	77.44	gold quality
lymph node	UBERON:0000029	76.71	gold quality
bone marrow cell	CL:0002092	76.38	gold quality
superficial temporal artery	UBERON:0001614	74.76	gold quality
caecum	UBERON:0001153	73.15	gold quality
palpebral conjunctiva	UBERON:0001812	71.35	gold quality
pleura	UBERON:0000977	70.94	gold quality
amniotic fluid	UBERON:0000173	70.93	gold quality
parietal pleura	UBERON:0002400	70.69	gold quality
lower lobe of lung	UBERON:0008949	70.65	gold quality
gall bladder	UBERON:0002110	70.40	gold quality
visceral pleura	UBERON:0002401	69.28	gold quality
lung	UBERON:0002048	68.61	gold quality
germinal epithelium of ovary	UBERON:0001304	68.31	gold quality
right lung	UBERON:0002167	68.19	gold quality
jejunal mucosa	UBERON:0000399	68.17	silver quality
epithelium of nasopharynx	UBERON:0001951	67.67	gold quality
nasopharynx	UBERON:0001728	67.66	gold quality
upper lobe of left lung	UBERON:0008952	66.92	gold quality
upper lobe of lung	UBERON:0008948	66.91	gold quality
mucosa of sigmoid colon	UBERON:0004993	65.52	silver quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	32.20
E-CURD-88	yes	26.46
E-HCAD-10	yes	25.91
E-CURD-46	yes	18.48
E-ANND-3	yes	16.88
E-CURD-112	yes	11.99
E-MTAB-8410	yes	10.10
E-CURD-122	yes	8.77
E-GEOD-130148	yes	7.22
E-MTAB-6379	no	1163.17
E-GEOD-124858	no	4.41

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

183 targeting GPR65, 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-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-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 30)

• GPR4 and TDAG8 overexpression in human tumors plays a role in driving or maintaining tumor formation (PMID:15221007)
• TDAG8 is one of the proton-sensing GPCRs coupling to adenylyl cyclase and psychosine, and its related lysosphingolipids behave as if they were antagonists against protein-sensing receptors, including TDAG8, GPR4, and OGR1. (PMID:15326175)
• TDAG8 may play biological roles in immune response and cellular transformation under conditions accompanying tissue acidosis. (PMID:15618224)
• Expression of TDAG8 by immune cells may regulate responses in acidic microenvironments. (PMID:15665078)
• At least partly, TDGA8 mediates extracellular acidification-induced inhibition of proinflammatory cytokine production through the Gs protein/cyclic AMP-dependent protein kinase A signaling pathway in transgenic mouse macrophages. (PMID:19234222)
• These results support the hypothesis that TDAG8 enhances tumor development by promoting adaptation to the acidic environment to enhance cell survival/proliferation. (PMID:20855608)
• Data suggest that one physiological function of TDAG8 is negative regulation of inflammation by inhibiting production of pro-inflammatory cytokines in T-lymphocytes and macrophages. (PMID:22445881)
• Acidosis promotes Bcl-2 family-mediated evasion of apoptosis: involvement of acid-sensing G protein-coupled receptor Gpr65 signaling to Mek/Erk. (PMID:22685289)
• GPR65 is a regulator upstream of MMP3, which is regulated by proton-sensing G-protein-coupled receptors (PMID:23707809)
• TDAG8 expression is decreased by more than 50%. (PMID:24152439)
• this study establishes a role for GPR65 in inflammatory bowel disease susceptibility and identify lysosomal dysfunction as a potentially causative element in pathogenesis (PMID:27287411)
• Study results suggest greater T cell death associated gene-8 (TDAG8) expression in patients with panic disorder compared to healthy subjects, and directly link TDAG8 expression and the severity of the panic disorder symptoms (PMID:28736033)
• TDAG8 functions as a contextual tumor suppressor down-regulated in hematological malignancies. (PMID:29017562)
• GPR65 is overexpressed in glioblastoma and its high expression predicts unfavorable clinical outcome for patients. (PMID:29223793)
• Panic disorder (PD) patients appear to display polymorphisms in the ACCN gene and elevated levels of TDAG8 mRNA. [systematic review, meta-analysis ] (PMID:30194289)
• this study shows that genetic polymorphisms of G protein-coupled receptor 65 gene are associated with ankylosing spondylitis in a Chinese Han population (PMID:30529363)
• we confirmed a significant association between the rare homozygote rs8005161 TT genotype and a diagnosis of ulcerative colitis. Our study did not identify biochemical changes in individuals with various genotypes of rs8005161, however we identified a lower activation of RhoA upon an acidic pH shift in inflammatory bowel disease patients. (PMID:30616622)
• T-cell death-associated gene 8 accelerates atherosclerosis by promoting vascular smooth muscle cell proliferation and migration. (PMID:32078831)
• Expression profiles of proton-sensing G-protein coupled receptors in common skin tumors. (PMID:32948783)
• The protective role of proton-sensing TDAG8 in the brain injury in a mouse ischemia reperfusion model. (PMID:33057165)
• Carbon dioxide inhibits UVB-induced inflammatory response by activating the proton-sensing receptor, GPR65, in human keratinocytes. (PMID:33431967)
• The evolution and mechanism of GPCR proton sensing. (PMID:33478938)
• Multilocus evaluation of genetic predictors of multiple sclerosis. (PMID:34656742)
• IBD-associated G protein-coupled receptor 65 variant compromises signalling and impairs key functions involved in inflammation. (PMID:35218908)
• GPR65 promotes intestinal mucosal Th1 and Th17 cell differentiation and gut inflammation through downregulating NUAK2. (PMID:35343079)
• MicroRNAs combined with the TLR4/TDAG8 mRNAs and proinflammatory cytokines are biomarkers for the rapid diagnosis of sepsis. (PMID:36102304)
• GPR65 inhibits human trophoblast cell adhesion through upregulation of MYLK and downregulation of fibronectin via cAMP-ERK signaling in a low pH environment. (PMID:37723567)
• Intestinal epithelial pH-sensing receptor GPR65 maintains mucosal homeostasis via regulating antimicrobial defense and restrains gut inflammation in inflammatory bowel disease. (PMID:37749885)
• Targeting GPR65 alleviates hepatic inflammation and fibrosis by suppressing the JNK and NF-kappaB pathways. (PMID:38001521)
• The proton-sensing receptors TDAG8 and GPR4 are differentially expressed in human and mouse oligodendrocytes: Exploring their role in neuroinflammation and multiple sclerosis. (PMID:38527054)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gpr65	ENSDARG00000045957
mus_musculus	Gpr65	ENSMUSG00000021886
rattus_norvegicus	Gpr65	ENSRNOG00000065590
caenorhabditis_elegans		WBGENE00016570

Paralogs (16): P2RY10 (ENSG00000078589), GPR18 (ENSG00000125245), F2RL3 (ENSG00000127533), GPR55 (ENSG00000135898), LPAR6 (ENSG00000139679), GPR17 (ENSG00000144230), LPAR4 (ENSG00000147145), CYSLTR2 (ENSG00000152207), F2RL2 (ENSG00000164220), F2RL1 (ENSG00000164251), CYSLTR1 (ENSG00000173198), GPR4 (ENSG00000177464), GPR35 (ENSG00000178623), F2R (ENSG00000181104), P2RY8 (ENSG00000182162), GPR20 (ENSG00000204882)

Protein

Protein identifiers

G-protein coupled receptor 65 — Q8IYL9 (reviewed: Q8IYL9)

Alternative names: Psychosine receptor, T-cell death-associated gene 8 protein

All UniProt accessions (2): Q8IYL9, B5B0C2

UniProt curated annotations — full annotation on UniProt →

Function. Proton-sensing G-protein coupled receptor activated by extracellular pH, which is required to monitor pH changes and generate adaptive reactions. Activated by an optimal pH of 7.4. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors, such as adenylate cyclase. GPR65 is mainly coupled to G(s) G proteins and mediates activation of adenylate cyclase activity. May also act as a receptor for the glycosphingolipid psychosine (PSY) and several related glycosphingolipids. Plays a role in immune response by maintaining lysosome function and regulating T-cell metabolism. Acts as a regulator of inflammation by mediating pH-sensing of extracellular acidification which takes place in inflamed tissues: activation regulates endo-lysosomal function of immune cells and T-cell metabolism. Constitutively active in endosomes and stimulates adenylate cyclase production from endosomes independently from extracellular pH changes.

Subcellular location. Cell membrane. Early endosome membrane. Late endosome membrane.

Tissue specificity. Predominantly expressed in thymus, spleen, lymph nodes, small intestine, lung, placenta and peripheral blood leukocytes.

Activity regulation. Activated by a network of residues that connects an extracellular-facing cavity to Glu-142, a conserved charged residue buried in the transmembrane core of the receptor. Protonation likely drives conformational changes in extracellular loop 2 (ECL2), which stabilizes movement of transmembrane 3 (TM3) and a series of rearrangements that connect the extracellular-facing cavity to Glu-142, a residue only conserved in proton-sensing G-protein coupled receptors. Activated by BTB09089, a positive allosteric modulator.

Domain organisation. A multitude of proton-sensing residues, which include extracellular histidine (His-10, His-14 and His-243) residues or triad of buried acidic residues (Asp-60, Glu-142, Asp-286), contribute to activation of the G-protein coupled receptor activity and pH sensitivity.

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

RefSeq proteins (1): NP_003599* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR005464	Psych_rcpt	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (58 total): mutagenesis site 12, helix 11, topological domain 8, transmembrane region 7, site 4, glycosylation site 3, sequence conflict 3, turn 3, disulfide bond 2, strand 2, chain 1, region of interest 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9BHL	ELECTRON MICROSCOPY	2.8
9JFT	ELECTRON MICROSCOPY	3.27

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IYL9-F1	82.53	0.45

Antibody-complex structures (SAbDab): 2 — 9BHL, 9JFT

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 (4): 10 (proton sensing); 14 (proton sensing); 142 (required for activation); 243 (proton sensing)

Disulfide bonds (2): 5–160, 87–170

Glycosylation sites (3): 2, 79, 166

Mutagenesis-validated functional residues (12):

Position	Phenotype
10	impaired proton sensing ability.
10	decreased proton-induced g-protein coupled receptor signaling; when associated with f-14 and f-243.
14	decreased proton-induced g-protein coupled receptor signaling; when associated with f-10 and f-243.
60	impaired ability to sense protons.
78	impaired proton sensing ability.
87	abolished proton sensing ability.
142	mimics the protonation state; induces a shift of the optimal ph for activation.
160	abolished proton sensing ability.
172	decreased proton-induced g-protein coupled receptor signaling.
243	decreased activation by protons. decreased proton-induced g-protein coupled receptor signaling; when associated with f-1
273	decreased proton-induced g-protein coupled receptor signaling.
286	impaired ability to sense protons.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-416476	G alpha (q) signalling events

MSigDB gene sets: 386 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, NKX25_02, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, MODULE_64, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, MORI_IMMATURE_B_LYMPHOCYTE_UP, GOBP_REGULATION_OF_T_HELPER_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION

GO Biological Process (10): apoptotic process (GO:0006915), immune response (GO:0006955), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), response to acidic pH (GO:0010447), positive regulation of interleukin-22 production (GO:0032746), positive regulation of T-helper cell differentiation (GO:0045624), positive regulation of stress fiber assembly (GO:0051496), cellular response to acidic pH (GO:0071468), signal transduction (GO:0007165)

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

GO Cellular Component (5): plasma membrane (GO:0005886), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
GPCR ligand binding	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endosome membrane	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
immune system process	1
response to stimulus	1
G protein-coupled receptor activity	1
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
response to pH	1
positive regulation of cytokine production	1
interleukin-22 production	1
regulation of interleukin-22 production	1
T-helper cell differentiation	1
positive regulation of CD4-positive, alpha-beta T cell differentiation	1
regulation of T-helper cell differentiation	1
positive regulation of immune response	1
positive regulation of actin filament bundle assembly	1
stress fiber assembly	1
regulation of stress fiber assembly	1
response to acidic pH	1
cellular response to pH	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
membrane	1
cell periphery	1
early endosome	1
late endosome	1
endomembrane system	1
cytoplasmic vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1596 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPR65	ASIC3	Q9UHC3	582
GPR65	GLP1R	P43220	475
GPR65	PDE8B	O95263	455
GPR65	LMOD1	P29536	429
GPR65	CD5L	O43866	425
GPR65	GPR151	Q8TDV0	420
GPR65	TRPV1	Q8NER1	418
GPR65	PIK3R1	P27986	416
GPR65	ASIC4	Q96FT7	414
GPR65	GPR45	Q9Y5Y3	413
GPR65	SMARCD3	Q6STE5	399
GPR65	HSPB2	Q16082	399
GPR65	GATM	P50440	397
GPR65	ASIC2	Q16515	392
GPR65	GPR84	Q9NQS5	392

IntAct

3 interactions, top by confidence:

A	B	Type	Score
GPR65	CYGB	psi-mi:“MI:0915”(physical association)	0.400
GPR65		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (2): CYGB (Affinity Capture-MS), GPR65 (Affinity Capture-RNA)

ESM2 similar proteins: A1A5S3, A5PLE7, B0UXR0, B5X337, F5HDK1, F5HF62, F8VQN3, O00421, O18982, O97663, P09703, P32249, P35351, P35374, P46002, P49685, P50052, P51676, P56412, P69332, P69333, Q01035, Q0II78, Q0VDU3, Q14330, Q1RMI1, Q28929, Q3T0E9, Q3U507, Q4R613, Q6IYF9, Q75ZH0, Q83207, Q89609, Q8BZR0, Q8IYL9, Q8K1Z6, Q95N03, Q96P67, Q98146

Diamond homologs: A0A4W3GG95, A0A6I8PUB9, A6QLE7, D4A7K7, E7FEL0, E9QJ73, O00254, O08675, O46685, P0C0W8, P0C5J4, P32246, P32249, P32250, P34996, P35366, P35383, P41231, P41232, P46093, P47900, P48042, P49650, P49651, P49652, P50132, P56482, P58826, P59902, P79928, P97266, Q149R9, Q15743, Q1JQB3, Q2Y2P0, Q3U6B2, Q3ZC80, Q4G072, Q4KLH9, Q5E9H8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GPR65	“up-regulates activity”	GNAI1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

313 predictions. Top by Δscore:

Variant	Effect	Δscore
14:88005218:TATGG:T	donor_gain	1.0000
14:88005219:ATGG:A	donor_gain	1.0000
14:88005220:TGG:T	donor_gain	1.0000
14:88005221:GG:G	donor_gain	1.0000
14:88005221:GGG:G	donor_gain	1.0000
14:88005222:GG:G	donor_gain	1.0000
14:88005223:G:GA	donor_loss	1.0000
14:88005223:G:GG	donor_gain	1.0000
14:88005224:T:A	donor_loss	0.9900
14:88005592:G:GG	donor_gain	0.9700
14:88005591:A:AG	donor_gain	0.9600
14:88005596:A:G	donor_gain	0.9600
14:88013860:A:G	acceptor_gain	0.9500
14:88010387:A:AG	acceptor_gain	0.9400
14:88010388:G:GG	acceptor_gain	0.9400
14:88007323:A:G	donor_gain	0.9300
14:88005223:G:T	donor_gain	0.9200
14:88005588:TC:T	donor_gain	0.9100
14:88005589:CC:C	donor_gain	0.9100
14:88010388:GAA:G	acceptor_gain	0.8900
14:88010387:AGAAG:A	acceptor_gain	0.8800
14:88010388:GAAGG:G	acceptor_gain	0.8800
14:88013859:A:AG	acceptor_gain	0.8800
14:88007203:ATTTG:A	acceptor_gain	0.8600
14:88010388:GA:G	acceptor_gain	0.8600
14:88007203:ATTT:A	acceptor_gain	0.8000
14:88010383:TTACA:T	acceptor_loss	0.7900
14:88010384:TACAG:T	acceptor_loss	0.7900
14:88010385:ACAGA:A	acceptor_loss	0.7900
14:88010387:A:T	acceptor_loss	0.7900

AlphaMissense

2232 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:88010929:A:C	S28R	0.998
14:88010931:C:A	S28R	0.998
14:88010931:C:G	S28R	0.998
14:88011087:G:C	W80C	0.998
14:88011087:G:T	W80C	0.998
14:88011685:A:C	S280R	0.998
14:88011687:T:A	S280R	0.998
14:88011687:T:G	S280R	0.998
14:88011010:A:C	S55R	0.996
14:88011012:T:A	S55R	0.996
14:88011012:T:G	S55R	0.996
14:88011250:A:C	S135R	0.996
14:88011252:C:A	S135R	0.996
14:88011252:C:G	S135R	0.996
14:88011562:T:C	F239L	0.996
14:88011564:T:A	F239L	0.996
14:88011564:T:G	F239L	0.996
14:88011106:T:A	C87S	0.995
14:88011107:G:C	C87S	0.995
14:88011148:A:C	S101R	0.995
14:88011150:C:A	S101R	0.995
14:88011150:C:G	S101R	0.995
14:88011182:G:C	R112P	0.995
14:88011262:T:A	W139R	0.995
14:88011262:T:C	W139R	0.995
14:88011355:T:A	C170S	0.995
14:88011356:G:C	C170S	0.995
14:88011569:C:G	P241R	0.995
14:88011085:T:A	W80R	0.994
14:88011085:T:C	W80R	0.994

dbSNP variants (sampled 300 via entrez): RS1000069220 (14:88013798 T>A), RS1000427539 (14:88004935 T>C), RS1000460088 (14:88005235 T>A,C), RS1000530192 (14:88010509 G>A), RS1000596884 (14:88012310 C>A,T), RS1000984330 (14:88010208 C>T), RS1001575642 (14:88005736 A>G), RS1001873770 (14:88007602 C>T), RS1001919337 (14:88004164 A>G), RS1002366983 (14:88010937 A>G), RS1002687522 (14:88004737 C>G), RS1002833625 (14:88005518 G>A), RS1003012283 (14:88007047 G>A,C,T), RS1003479568 (14:88014311 G>A), RS1003720362 (14:88003574 T>G)

Disease associations

OMIM: gene MIM:604620 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000879_38	Crohn’s disease	4.000000e-18
GCST001198_21	Multiple sclerosis	2.000000e-10
GCST001725_48	Inflammatory bowel disease	2.000000e-14
GCST002518_6	Food antigen IgG levels	6.000000e-07
GCST004131_90	Inflammatory bowel disease	3.000000e-11
GCST004132_113	Crohn’s disease	5.000000e-12
GCST005529_2	Ankylosing spondylitis	2.000000e-10
GCST005529_59	Ankylosing spondylitis	2.000000e-10
GCST006273_2	Diastolic blood pressure night-to-day ratio in hypertension	3.000000e-06
GCST006575_6	Takayasu arteritis	6.000000e-06
GCST007001_8	Cerebrospinal AB1-42 levels in normal cognition	5.000000e-07
GCST009304_6	Degraded stimulus continuous performance test score	3.000000e-06
GCST009305_1	California verbal learning test score	3.000000e-06
GCST010991_19	Parkinson’s disease	6.000000e-10
GCST90002382_228	Eosinophil percentage of white cells	4.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0005844	response to dietary antigen
EFO:0006945	diastolic blood pressure change measurement
EFO:0004670	beta-amyloid 1-42 measurement
EFO:0007636	attention function measurement
EFO:0004874	memory performance
EFO:0007991	eosinophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3714081 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

11 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 92,237 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1200492	NEFAZODONE HYDROCHLORIDE	4	5,428
CHEMBL1200776	CINACALCET HYDROCHLORIDE	4	1,220
CHEMBL1201082	FLUOXETINE HYDROCHLORIDE	4	18,871
CHEMBL1263	SALMETEROL	4	40,383
CHEMBL1471	APREPITANT	4	901
CHEMBL2111101	PIMAVANSERIN	4	1,357
CHEMBL567	PERPHENAZINE	4	21,883
CHEMBL2107572	TECALCET HYDROCHLORIDE	2	100
CHEMBL232656	BX 471 FREE BASE	2	191
CHEMBL405355	NIGULDIPINE	2	1,802
CHEMBL582857	NELIVAPTAN	2	101

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 emerging pharmacology

ChEMBL bioactivities

58 potent at pChembl≥5 of 58 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.44	IC50	364.8	nM	CHEMBL449588
6.30	IC50	500	nM	CHEMBL5417806
6.30	IC50	500	nM	CHEMBL5420624
6.30	IC50	500	nM	CHEMBL5427600
6.30	IC50	500	nM	CHEMBL5404390
6.30	IC50	500	nM	CHEMBL5437369
6.30	IC50	500	nM	CHEMBL5422604
6.30	IC50	500	nM	CHEMBL5424723
6.30	IC50	500	nM	CHEMBL5421727
6.30	IC50	500	nM	CHEMBL5437775
6.30	IC50	500	nM	CHEMBL5406392
6.30	IC50	500	nM	CHEMBL5398106
6.30	IC50	500	nM	CHEMBL5406035
6.30	IC50	500	nM	CHEMBL5400228
6.30	IC50	500	nM	CHEMBL5431825
6.30	IC50	500	nM	CHEMBL5433744
6.30	IC50	500	nM	CHEMBL5400100
6.30	IC50	500	nM	CHEMBL5402018
6.30	IC50	500	nM	CHEMBL5413335
6.30	IC50	500	nM	CHEMBL5403385
6.30	IC50	500	nM	CHEMBL5407784
6.30	IC50	500	nM	CHEMBL5435598
6.30	IC50	500	nM	CHEMBL5440522
6.30	EC50	501.2	nM	CHEMBL1492152
5.95	IC50	1115	nM	CP-96345
5.90	EC50	1265	nM	CHEMBL5076314
5.84	IC50	1449	nM	CHEMBL1256876
5.73	IC50	1874	nM	APREPITANT
5.66	IC50	2190	nM	TECALCET HYDROCHLORIDE
5.65	IC50	2251	nM	CHEMBL329650
5.63	IC50	2334	nM	NORDIHYDROGUAIARETIC ACID
5.62	IC50	2385	nM	CHEMBL103769
5.62	IC50	2374	nM	BX 471 FREE BASE
5.62	IC50	2392	nM	NELIVAPTAN
5.61	IC50	2463	nM	SALMETEROL
5.58	IC50	2629	nM	CHEMBL103769
5.58	IC50	2608	nM	FLUOXETINE HYDROCHLORIDE
5.54	IC50	2905	nM	CHEMBL1766103
5.53	IC50	2939	nM	CHEMBL5075931
5.52	IC50	3014	nM	CINACALCET HYDROCHLORIDE
5.51	IC50	3081	nM	NIGULDIPINE
5.48	IC50	3316	nM	PURVALANOLA
5.47	IC50	3389	nM	NEFAZODONE HYDROCHLORIDE
5.47	IC50	3350	nM	CHEMBL5092226
5.46	IC50	3478	nM	CHEMBL531742
5.45	IC50	3540	nM	PIMAVANSERIN
5.42	IC50	3849	nM	CHEMBL2018875
5.41	IC50	3901	nM	CHEMBL5089005
5.40	IC50	3944	nM	PERPHENAZINE
5.40	IC50	3987	nM	CHEMBL5084234

PubChem BioAssay actives

2 with measured affinity, of 25 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[4-(3,4-dimethoxyphenyl)-1,3-thiazol-2-yl]-2-(1H-1,2,4-triazol-5-ylsulfanyl)acetamide	2161961: Antagonist activity against GPR65 (unknown origin) transfected in human HEK293T cells incubated for 15 mins by luminescence counter analysis	ec50	0.5012	uM
3-[(2,4-dichlorophenyl)methylsulfanyl]-1,6-dimethylpyridazino[4,5-e][1,3,4]thiadiazin-5-one	2161961: Antagonist activity against GPR65 (unknown origin) transfected in human HEK293T cells incubated for 15 mins by luminescence counter analysis	ec50	7.7625	uM

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sulforaphane	decreases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	increases expression	1
3,4,3’,4’-tetrachlorobiphenyl	affects expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	decreases expression, increases abundance	1
Carmustine	increases expression	1
Cisplatin	increases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Methyl Methanesulfonate	decreases expression	1
Nickel	increases expression	1
Oxygen	decreases expression	1
Ozone	affects expression, increases abundance	1
Tretinoin	increases expression	1
Aflatoxin B1	increases methylation	1
Sodium Selenite	increases expression	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	decreases expression, increases abundance	1

ChEMBL screening assays

17 unique, capped per target: 14 functional, 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3813383	Functional	Antagonist activity at N-terminal HA-tagged TDAG8 receptor (unknown origin) expressed in HEK293 cells assessed as inhibition of pH dependent cAMP response element-driven transcriptional activity at >1 uM at pH 7.2 incubated for 6 hrs by dua	Identification of a Potent and Selective GPR4 Antagonist as a Drug Lead for the Treatment of Myocardial Infarction. — ACS Med Chem Lett
CHEMBL4883464	Binding	PRESTO-Tango GPCRome screening (GPR65)	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_KX70	PathHunter CHO-K1 GPR65 beta-arrestin	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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