ADGRG2

Summary

ADGRG2 (adhesion G protein-coupled receptor G2, HGNC:4516) is a protein-coding gene on chromosome Xp22.13, encoding Adhesion G-protein coupled receptor G2 (Q8IZP9). Adhesion G-protein coupled receptor (aGPCR) for steroid hormones, such as dehydroepiandrosterone (DHEA; also named 3beta-hydroxyandrost-5-en-17-one) and androstenedione.

This gene encodes a member of the G protein-coupled receptor family described as an epididymis-specific transmembrane protein. The encoded protein may be proteolytically processed as it contains a motif shown to be a protein scission motif in some members of this family (PMID: 11973329). Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10149 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital bilateral absence of vas deferens (Supportive, GenCC)
• Clinical variants (ClinVar): 374 total — 15 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 10
• Druggable target: yes
• MANE Select transcript: NM_001079858

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4516
Approved symbol	ADGRG2
Name	adhesion G protein-coupled receptor G2
Location	Xp22.13
Locus type	gene with protein product
Status	Approved
Aliases	HE6, TM7LN2, EDDM6
Ensembl gene	ENSG00000173698
Ensembl biotype	protein_coding
OMIM	300572
Entrez	10149

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 24 protein_coding, 1 retained_intron

ENST00000340581, ENST00000354791, ENST00000356606, ENST00000357544, ENST00000357991, ENST00000360279, ENST00000379869, ENST00000379873, ENST00000379876, ENST00000379878, ENST00000479496, ENST00000869010, ENST00000916544, ENST00000916545, ENST00000916546, ENST00000916547, ENST00000916548, ENST00000916549, ENST00000916550, ENST00000916551, ENST00000916552, ENST00000916553, ENST00000916554, ENST00000916555, ENST00000971549

RefSeq mRNA: 9 — MANE Select: NM_001079858 NM_001079858, NM_001079859, NM_001079860, NM_001184833, NM_001184834, NM_001184835, NM_001184836, NM_001184837, NM_005756

CCDS: CCDS14191, CCDS43921, CCDS43922, CCDS43923, CCDS55376, CCDS55377, CCDS55378, CCDS55379

Canonical transcript exons

ENST00000379869 — 29 exons

Exon	Start	End
ENSE00001231797	19037467	19037490
ENSE00001231812	19040189	19040224
ENSE00001231821	19068717	19068835
ENSE00001231843	19030984	19031037
ENSE00001309691	19033613	19033654
ENSE00001313815	19035942	19035977
ENSE00001370737	19082702	19082746
ENSE00001482777	19037589	19037636
ENSE00001597688	18994896	18995048
ENSE00001603100	19007980	19008123
ENSE00001618383	19009626	19009782
ENSE00001625348	19019599	19019665
ENSE00001633690	19006220	19006265
ENSE00001635524	19002846	19003114
ENSE00001643995	18998996	18999279
ENSE00001654299	18999861	18999960
ENSE00001699907	19006002	19006105
ENSE00001721711	19010613	19010778
ENSE00001775456	19004758	19004879
ENSE00001780835	19007235	19007357
ENSE00001793720	19013686	19014074
ENSE00001799993	18996051	18996152
ENSE00003493785	19023909	19023948
ENSE00003608635	19023416	19023453
ENSE00003612012	19021104	19021198
ENSE00003617702	19027219	19027274
ENSE00003674492	19028183	19028238
ENSE00003846715	19122442	19122468
ENSE00003848047	18989307	18991048

Expression profiles

Bgee: expression breadth ubiquitous, 182 present calls, max score 99.98.

FANTOM5 (CAGE): breadth broad, TPM avg 1.4077 / max 351.6425, expressed in 286 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198610	0.7381	155
198611	0.5235	164
198612	0.0899	20
198609	0.0394	14
198608	0.0168	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	99.98	gold quality
caput epididymis	UBERON:0004358	99.88	gold quality
parotid gland	UBERON:0001831	98.00	gold quality
cauda epididymis	UBERON:0004360	98.00	gold quality
synovial joint	UBERON:0002217	93.47	gold quality
cartilage tissue	UBERON:0002418	90.13	gold quality
layer of synovial tissue	UBERON:0007616	86.65	gold quality
dorsal root ganglion	UBERON:0000044	83.61	gold quality
pancreatic ductal cell	CL:0002079	80.26	gold quality
epithelial cell of pancreas	CL:0000083	79.93	silver quality
islet of Langerhans	UBERON:0000006	79.68	gold quality
epithelium of nasopharynx	UBERON:0001951	78.79	gold quality
oocyte	CL:0000023	78.61	gold quality
germinal epithelium of ovary	UBERON:0001304	77.34	gold quality
secondary oocyte	CL:0000655	75.93	gold quality
cortical plate	UBERON:0005343	74.75	gold quality
seminal vesicle	UBERON:0000998	74.45	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	74.36	gold quality
tendon of biceps brachii	UBERON:0008188	74.05	gold quality
calcaneal tendon	UBERON:0003701	73.92	gold quality
trigeminal ganglion	UBERON:0001675	73.48	gold quality
lymph node	UBERON:0000029	72.26	gold quality
mucosa of stomach	UBERON:0001199	72.12	gold quality
saliva-secreting gland	UBERON:0001044	71.03	gold quality
descending thoracic aorta	UBERON:0002345	71.00	gold quality
endometrium	UBERON:0001295	70.93	gold quality
tendon	UBERON:0000043	70.51	gold quality
peritoneum	UBERON:0002358	70.23	gold quality
omental fat pad	UBERON:0010414	70.16	gold quality
right uterine tube	UBERON:0001302	69.66	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.23

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, RUNX2

miRNA regulators (miRDB)

125 targeting ADGRG2, 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-5692A	100.00	74.40	6850
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-205-3P	99.92	69.92	3165

Literature-anchored findings (GeneRIF, showing 14)

• Knockdown of ADGRG2 breast cancer cell lines resulted in a strong reduction in cell adhesion and subsequent cell migration which was associated with a selective reduction in RelB. (PMID:26321231)
• study confirms the crucial role of ADGRG2 in human male fertility and brings new insight into congenital obstructive azoospermia pathogenesis; in men with CBAVD who are CFTR-negative, ADGRG2 testing could allow for appropriate genetic counseling with regard to the X-linked transmission of the molecular defect (PMID:27476656)
• GPR64 is expressed on the cell surface of parathyroid cells, is overexpressed in parathyroid tumors, and physically interacts with the CaSR. (PMID:27760455)
• The expression of GPR64 was increased in human endometrial stromal cells (hESCs) during in vitro decidualization. Interestingly, siRNA-mediated knockdown of GPR64 in hESCs remarkably reduced decidualization. These results suggest that Gpr64 has a crucial role in the decidualization of endometrial stromal cells. (PMID:28694502)
• identified two missense variants in two congenital bilateral absence of the vas deferens (CBAVD) patients (c.G1709A, p.C570Y; and c.A2968G, p.K990E); study did not find any potential pathogenic CFTR variants, implying the ADGRG2 variants are the genetic cause in these patients (PMID:28805948)
• Study identified novel nonsense variant c.2440C > T(p.Arg814*) in X-linked gene ADGRG2 as cause of obstructive azoospermia in a large Pakistani family. (PMID:30389958)
• G-protein coupled receptor 64 (GPR64) levels are remarkably lower in endometrial carcinoma samples compared to control. Depletion of GPR64 reveals an increase of colony formation ability, cell proliferation, cell migration, and invasion activity in Ishikawa and HEC1A cells. The expression of Connexin 43 is reduced through activation of AMP-activated protein kinase in tumor cells with GPR64-deficiency. (PMID:31412816)
• data suggest that GPCR64 N-terminal fragment not only shields the tethered agonist to prevent G protein signaling but also confers a conformation that inhibits the interaction with beta-arrestins and the consequent endocytosis and sustained signaling from endosomes (PMID:31502283)
• Novel ADGRG2 truncating variants in patients with X-linked congenital absence of vas deferens. (PMID:31845523)
• A novel hemizygous loss-of-function mutation in ADGRG2 causes male infertility with congenital bilateral absence of the vas deferens. (PMID:32314195)
• Conserved residues in the extracellular loop 2 regulate Stachel-mediated activation of ADGRG2. (PMID:34234254)
• Structures of the ADGRG2-Gs complex in apo and ligand-bound forms. (PMID:35982227)
• A novel ADGRG2 truncating variant associated with X-linked obstructive azoospermia in a large Chinese pedigree. (PMID:37273165)
• Adhesion G Protein-Coupled Receptor G2 Promotes Hepatocellular Carcinoma Progression and Serves as a Neutrophil-Related Prognostic Biomarker. (PMID:38069309)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	adgrg4b	ENSDARG00000094386
mus_musculus	Adgrg2	ENSMUSG00000031298
rattus_norvegicus	Adgrg2	ENSRNOG00000032472

Paralogs (42): CALCR (ENSG00000004948), GIPR (ENSG00000010310), ADGRA2 (ENSG00000020181), CALCRL (ENSG00000064989), GLP2R (ENSG00000065325), ADGRF5 (ENSG00000069122), ADGRL1 (ENSG00000072071), ADCYAP1R1 (ENSG00000078549), SCTR (ENSG00000080293), VIPR2 (ENSG00000106018), CRHR2 (ENSG00000106113), GHRHR (ENSG00000106128), ADGRD1 (ENSG00000111452), GLP1R (ENSG00000112164), ADGRG6 (ENSG00000112414), VIPR1 (ENSG00000114812), ADGRL2 (ENSG00000117114), CRHR1 (ENSG00000120088), ADGRB2 (ENSG00000121753), ADGRE5 (ENSG00000123146), ADGRE2 (ENSG00000127507), ADGRE3 (ENSG00000131355), ADGRB3 (ENSG00000135298), PTH2R (ENSG00000144407), ADGRG7 (ENSG00000144820), ADGRL3 (ENSG00000150471), ADGRA3 (ENSG00000152990), ADGRF1 (ENSG00000153292), ADGRF4 (ENSG00000153294), ADGRG4 (ENSG00000156920), ADGRG5 (ENSG00000159618), PTH1R (ENSG00000160801), ADGRL4 (ENSG00000162618), EVA1C (ENSG00000166979), ADGRF3 (ENSG00000173567), ADGRE1 (ENSG00000174837), ADGRD2 (ENSG00000180264), ADGRB1 (ENSG00000181790), ADGRG3 (ENSG00000182885), ADGRA1 (ENSG00000197177)

Protein

Protein identifiers

Adhesion G-protein coupled receptor G2 — Q8IZP9 (reviewed: Q8IZP9)

Alternative names: G-protein coupled receptor 64, Human epididymis-specific protein 6

All UniProt accessions (1): Q8IZP9

UniProt curated annotations — full annotation on UniProt →

Function. Adhesion G-protein coupled receptor (aGPCR) for steroid hormones, such as dehydroepiandrosterone (DHEA; also named 3beta-hydroxyandrost-5-en-17-one) and androstenedione. Involved in a signal transduction pathway controlling epididymal function and male fertility. 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. ADGRG2 is coupled to G(s) G proteins and mediates activation of adenylate cyclase activity. Also able to couple with G(q) G proteins in vitro. Together with CFTR, required to promote fluid reabsorption within efferent ductule.

Subunit / interactions. Heterodimer of 2 chains generated by proteolytic processing; the large extracellular N-terminal fragment and the membrane-bound C-terminal fragment predominantly remain associated and non-covalently linked. Interacts with CFTR.

Subcellular location. Apical cell membrane.

Tissue specificity. Epididymis-specific expression (at protein level). Both subunits are associated with apical membranes of efferent ductule and proximal epididymal duct epithelia. Mainly expressed in the nonciliated principal cells of the proximal excurrent ducts. Specifically over-expressed in Ewing sarcomas but also up-regulated in a number of carcinomas derived from prostate, kidney or lung.

Post-translational modifications. Proteolytically cleaved into 2 subunits, an extracellular subunit and a seven-transmembrane subunit. Highly glycosylated.

Disease relevance. Congenital bilateral aplasia of the vas deferens, X-linked (CBAVDX) [MIM:300985] A disease characterized by bilateral absence of vas deferens, obstructive azoospermia, and infertility. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Forms a heterodimer of 2 chains generated by proteolytic processing that remain associated through non-covalent interactions mediated by the GAIN-B domain. In the inactivated receptor, the Stachel sequence (also named stalk) is embedded in the GAIN-B domain, where it adopts a beta-strand conformation. On activation, the Stachel moves into the 7 transmembrane region and adopts a twisted hook-shaped configuration that forms contacts within the receptor, leading to coupling of a G-alpha protein, which activates signaling. The cleaved GAIN-B and N-terminal domains can then dissociate from the rest of the receptor. Deoxycorticosterone (DOC) acts as an antagonist of ADGRG2.

Domain organisation. The Stachel sequence (also named stalk) in the C-terminal part of the extracellular domain (ECD) functions as a tethered agonist. In the inactivated receptor, the Stachel sequence (also named stalk) is embedded in the GAIN-B domain, where it adopts a beta-strand conformation. On activation, the Stachel moves into the 7 transmembrane region and adopts a twisted hook-shaped configuration that forms contacts within the receptor, leading to coupling of a G-alpha protein, which activates signaling.

Similarity. Belongs to the G-protein coupled receptor 2 family. Adhesion G-protein coupled receptor (ADGR) subfamily.

Isoforms (10)

UniProt ID	Names	Canonical?
Q8IZP9-1	1, Long splice variant	yes
Q8IZP9-2	2
Q8IZP9-3	3, d1
Q8IZP9-4	4, 24
Q8IZP9-5	5, 23
Q8IZP9-6	6, d3
Q8IZP9-7	7, d2
Q8IZP9-8	8, 21
Q8IZP9-9	9, Delta exon 28
Q8IZP9-10	10

RefSeq proteins (9): NP_001073327, NP_001073328, NP_001073329, NP_001171762, NP_001171763, NP_001171764, NP_001171765, NP_001171766, NP_005747 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000203	GPS	Conserved_site
IPR000832	GPCR_2_secretin-like	Family
IPR017981	GPCR_2-like_7TM	Domain
IPR017983	GPCR_2_secretin-like_CS	Conserved_site
IPR046338	GAIN_dom_sf	Homologous_superfamily
IPR057244	GAIN_B	Domain
IPR058772	ADGRG2_N	Domain
IPR058857	GAIN_ADGRG2/6	Domain

Pfam: PF00002, PF01825, PF26152, PF26574

UniProt features (90 total): glycosylation site 21, mutagenesis site 16, splice variant 9, sequence variant 9, topological domain 8, transmembrane region 7, region of interest 4, chain 3, compositionally biased region 3, disulfide bond 3, sequence conflict 2, signal peptide 1, domain 1, binding site 1, site 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IZP9-F1	62.76	0.12

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): 606–607 (cleavage; by autolysis)

Ligand- & substrate-binding residues (1): 868

Post-translational modifications (1): 1010

Disulfide bonds (3): 570–601, 589–603, 694–778

Glycosylation sites (21): 44, 85, 99, 111, 117, 144, 162, 186, 194, 357, 370, 435, 438, 456, 461, 528, 542, 547, 551, 597 …

Mutagenesis-validated functional residues (16):

Position	Phenotype
679	decreased activation by dehydroepiandrosterone.
705	decreased activation by dehydroepiandrosterone.
720	impaired ability to activate g-alpha protein g(s) without affecting ability to activate g(q).
727	impaired ability to activate g-alpha protein g(s) without affecting ability to activate g(q).
730	impaired ability to activate g-alpha protein g(q) without affecting ability to activate g(s).
779–780	accelerated degradation; reduced expression to the cell surface; reduced ability to activate g-alpha g(s).
779	accelerated degradation; reduced expression to the cell surface; reduced ability to activate g-alpha g(s).
780	accelerated degradation; reduced expression to the cell surface; reduced ability to activate g-alpha g(s).
786	increased ability to activate g-proteins.
787	increased ability to activate g-proteins.
790	decreased ability to activate g-proteins.
794	decreased ability to activate g-proteins.
825–826	impaired ability to activate g-alpha protein g(q) without affecting ability to activate g(s).
846	decreased activation by dehydroepiandrosterone.
864	decreased activation by dehydroepiandrosterone.
868	decreased activation by dehydroepiandrosterone.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 138 (showing top): WALLACE_PROSTATE_CANCER_RACE_UP, LI_WILMS_TUMOR, GOCC_CELL_SURFACE, GAUSSMANN_MLL_AF4_FUSION_TARGETS_E_UP, GOBP_MALE_GAMETE_GENERATION, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, BROWNE_HCMV_INFECTION_24HR_UP, MCLACHLAN_DENTAL_CARIES_DN, BLALOCK_ALZHEIMERS_DISEASE_UP, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOCC_APICAL_PLASMA_MEMBRANE, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, CCCAGAG_MIR326, GOBP_PHOSPHOLIPASE_C_ACTIVATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (7): cell surface receptor signaling pathway (GO:0007166), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), spermatogenesis (GO:0007283), spermatid development (GO:0007286), signal transduction (GO:0007165)

GO Molecular Function (3): G protein-coupled receptor activity (GO:0004930), transmembrane signaling receptor activity (GO:0004888), protein binding (GO:0005515)

GO Cellular Component (6): cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), apical plasma membrane (GO:0016324), extracellular exosome (GO:0070062)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
signal transduction	2
G protein-coupled receptor signaling pathway	2
G protein-coupled receptor activity	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
phospholipase C activator activity	1
developmental process involved in reproduction	1
male gamete generation	1
germ cell development	1
spermatid differentiation	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transmembrane signaling receptor activity	1
signaling receptor activity	1
binding	1
cytoplasm	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1
extracellular vesicle	1

Protein interactions and networks

STRING

686 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADGRG2	SCT	P09683	691
ADGRG2	CFTR	P13569	680
ADGRG2	ARRB1	P49407	586
ADGRG2	GNAQ	P50148	543
ADGRG2	GNA12	Q03113	531
ADGRG2	TEDDM1	Q5T9Z0	520
ADGRG2	CASR	P41180	513
ADGRG2	PABIR3	Q6P4D5	507
ADGRG2	SAGE1	Q9NXZ1	398
ADGRG2	SLC26A9	Q7LBE3	395
ADGRG2	CRISP1	P54107	390
ADGRG2	CDK16	Q00536	387
ADGRG2	DIAPH2	O60879	385
ADGRG2	TENM1	Q9UKZ4	385
ADGRG2	PCDH1	Q08174	383

IntAct

14 interactions, top by confidence:

A	B	Type	Score
ADGRG2	CFAP69	psi-mi:“MI:0914”(association)	0.350
NIPA1	UNC119B	psi-mi:“MI:0914”(association)	0.350
NIPAL3	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC15A2	LGALS8	psi-mi:“MI:0914”(association)	0.350
SLC22A5	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SLC22A9	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC29A2	EIF3CL	psi-mi:“MI:0914”(association)	0.350
SLC2A2	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC35F1	C15orf61	psi-mi:“MI:0914”(association)	0.350
SLC35F3	TMEM223	psi-mi:“MI:0914”(association)	0.350
SLC39A4	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC49A4	AP3B1	psi-mi:“MI:0914”(association)	0.350
SLC7A1	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (23): INTS1 (Affinity Capture-MS), ATM (Affinity Capture-MS), SLC7A3 (Affinity Capture-MS), CERS6 (Affinity Capture-MS), CFAP69 (Affinity Capture-MS), GMIP (Affinity Capture-MS), GPR50 (Affinity Capture-MS), RIF1 (Affinity Capture-MS), GPR89A (Affinity Capture-MS), ARFGEF1 (Affinity Capture-MS), TUBGCP4 (Affinity Capture-MS), GPR64 (Affinity Capture-MS), GPR64 (Affinity Capture-MS), GPR64 (Affinity Capture-MS), GPR64 (Affinity Capture-MS)

ESM2 similar proteins: A7E2Z9, A8K7I4, B7ZSK1, C6KFA3, P07911, P15396, P17301, P19218, P52787, P53710, Q14CN2, Q16819, Q1WIM2, Q2TU62, Q5T601, Q5VV43, Q5Y4N8, Q61549, Q62469, Q62929, Q66IR0, Q6DJ83, Q6F3F9, Q6PT52, Q6Q473, Q6QMG1, Q6YHK3, Q70VB1, Q862Z3, Q86SQ4, Q8BGZ8, Q8BLQ9, Q8BM96, Q8CJ11, Q8CJ12, Q8IZP9, Q8K4Z6, Q8N3J6, Q8TCW7, Q91X17

Diamond homologs: B7ZCC9, C6KFA3, G5ECX0, G5EDW2, O88917, O94910, O97817, O97827, O97831, Q2Q421, Q2Q426, Q3V3Z3, Q50DM5, Q50DM6, Q50DM7, Q50DM8, Q6F3F9, Q6QNK2, Q7SY09, Q80TR1, Q80TS3, Q86SQ3, Q86SQ4, Q86Y34, Q8CJ11, Q8CJ12, Q8IZF4, Q8IZF6, Q8IZP9, Q8JZZ7, Q8K209, Q8SQA4, Q923X1, Q9BY15, Q9ESC1, Q9HAR2, Q9HBW9, Q9HCU4, Q9QYP2, Q9R0M0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	1
Uncertain significance	109
Likely benign	19
Benign	6

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
1285394	NM_001079858.3(ADGRG2):c.2033_2035delinsACTCGTGGATTGCTCTG (p.Val678fs)	Pathogenic
1526767	GRCh37/hg19 Xp22.13-22.12(chrX:18645361-19678763)	Pathogenic
253013	NM_001079858.3(ADGRG2):c.2845del (p.Cys949fs)	Pathogenic
253014	NM_001079858.3(ADGRG2):c.2002_2006delinsAGA (p.Leu668fs)	Pathogenic
253015	NM_001079858.3(ADGRG2):c.1545dup (p.Glu516Ter)	Pathogenic
3243867	NC_000023.10:g.(?17393881)(20284750_?)del	Pathogenic
4279452	GRCh37/hg19 Xp22.31-21.3(chrX:6446580-24953919)x2	Pathogenic
443028	GRCh37/hg19 Xp22.33-11.21(chrX:168546-54996659)x1	Pathogenic
57649	GRCh38/hg38 Xp22.13-22.12(chrX:18660565-19743908)x1	Pathogenic
691628	NM_001079858.3(ADGRG2):c.2473C>T (p.Arg825Ter)	Pathogenic
691629	NM_001079858.3(ADGRG2):c.2096dup (p.Phe700fs)	Pathogenic
691630	NM_001079858.3(ADGRG2):c.251C>G (p.Ser84Ter)	Pathogenic
691631	NM_001079858.3(ADGRG2):c.1460del (p.Gly487fs)	Pathogenic
691632	NM_001079858.3(ADGRG2):c.1013del (p.Pro338fs)	Pathogenic
691633	NM_001079858.3(ADGRG2):c.1731_1839+373del	Pathogenic
2582758	NM_001079858.3(ADGRG2):c.366del (p.Phe122fs)	Likely pathogenic

SpliceAI

3873 predictions. Top by Δscore:

Variant	Effect	Δscore
X:18997270:C:CT	donor_gain	1.0000
X:18998990:GCTTA:G	donor_loss	1.0000
X:18998991:CTTAC:C	donor_loss	1.0000
X:18998992:TTA:T	donor_loss	1.0000
X:18998993:TACCT:T	donor_loss	1.0000
X:18998994:A:AT	donor_loss	1.0000
X:18999280:C:CC	acceptor_gain	1.0000
X:18999287:T:C	acceptor_gain	1.0000
X:18999287:T:TC	acceptor_gain	1.0000
X:18999289:G:GC	acceptor_gain	1.0000
X:18999859:A:AC	donor_gain	1.0000
X:18999860:C:CC	donor_gain	1.0000
X:19002902:TTG:T	donor_gain	1.0000
X:19006262:CATC:C	acceptor_gain	1.0000
X:19006266:C:CA	acceptor_loss	1.0000
X:19006266:C:CC	acceptor_gain	1.0000
X:19007174:CAAG:C	donor_gain	1.0000
X:19007197:T:TA	donor_gain	1.0000
X:19007367:CAAGA:C	acceptor_gain	1.0000
X:19007368:A:T	acceptor_gain	1.0000
X:19007371:A:C	acceptor_gain	1.0000
X:19007375:C:CT	acceptor_gain	1.0000
X:19007376:A:T	acceptor_gain	1.0000
X:19007975:TTTA:T	donor_loss	1.0000
X:19007976:TTA:T	donor_loss	1.0000
X:19007977:TA:T	donor_loss	1.0000
X:19007978:A:AT	donor_loss	1.0000
X:19007979:C:A	donor_loss	1.0000
X:19008016:AAC:A	donor_gain	1.0000
X:19008122:ACCTG:A	acceptor_loss	1.0000

AlphaMissense

6654 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:18998996:C:G	G872R	0.999
X:18998996:C:T	G872R	0.999
X:18999074:A:G	W846R	0.999
X:18999074:A:T	W846R	0.999
X:19002895:A:C	F727L	0.999
X:19002895:A:T	F727L	0.999
X:19002897:A:G	F727L	0.999
X:19002945:A:G	W711R	0.999
X:19002945:A:T	W711R	0.999
X:19006089:C:A	W584C	0.999
X:19006089:C:G	W584C	0.999
X:18996099:A:G	W890R	0.998
X:18996099:A:T	W890R	0.998
X:18996143:A:T	I875K	0.998
X:18999082:C:T	G843E	0.998
X:18999083:C:G	G843R	0.998
X:18999083:C:T	G843R	0.998
X:19002849:A:G	W743R	0.998
X:19002849:A:T	W743R	0.998
X:19002908:A:G	L723P	0.998
X:19006091:A:G	W584R	0.998
X:19006091:A:T	W584R	0.998
X:19006236:C:A	W573C	0.998
X:19006236:C:G	W573C	0.998
X:18996152:C:T	G872E	0.997
X:18999018:A:C	F864L	0.997
X:18999018:A:T	F864L	0.997
X:18999020:A:G	F864L	0.997
X:18999082:C:A	G843V	0.997
X:19002896:A:C	F727C	0.997

dbSNP variants (sampled 300 via entrez): RS1000036742 (X:19093285 G>A), RS1000115862 (X:19089598 CAA>C,CA), RS1000133152 (X:19040662 A>G), RS1000158701 (X:19015693 T>G), RS1000185551 (X:19020218 C>A), RS1000277663 (X:19101348 C>T), RS1000283214 (X:19074198 T>C), RS1000300321 (X:19010979 G>A), RS1000316503 (X:19028454 C>T), RS1000342325 (X:19074730 C>T), RS1000385588 (X:19002808 A>T), RS1000436528 (X:19027775 C>A), RS1000473248 (X:19001120 C>T), RS1000480547 (X:19018028 A>G), RS1000488337 (X:19064691 A>G)

Disease associations

OMIM: gene MIM:300572 | disease phenotypes: MIM:300985, MIM:300672, MIM:300844, MIM:302350, MIM:303600, MIM:306000, MIM:277180, MIM:312170, MIM:189600, MIM:213000

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital bilateral absence of vas deferens	Supportive	Autosomal recessive

Mondo (13): vas deferens, congenital bilateral aplasia of, X-linked (MONDO:0010511), developmental and epileptic encephalopathy, 2 (MONDO:0010396), intellectual disability, X-linked 19 (MONDO:0010447), Nance-Horan syndrome (MONDO:0010545), Coffin-Lowry syndrome (MONDO:0010561), glycogen storage disease IXa1 (MONDO:0010598), congenital bilateral aplasia of vas deferens from CFTR mutation (MONDO:0010178), pyruvate dehydrogenase E1-alpha deficiency (MONDO:0010717), intellectual disability (MONDO:0001071), microcephaly (MONDO:0001149), inherited torticollis (MONDO:0008583), isolated cerebellar hypoplasia/agenesis (MONDO:0008939), congenital bilateral absence of vas deferens (MONDO:0018801)

Orphanet (12): Coffin-Lowry syndrome (Orphanet:192), Early infantile developmental and epileptic encephalopathy (Orphanet:1934), Glycogen storage disease due to liver phosphorylase kinase deficiency (Orphanet:264580), West syndrome (Orphanet:3451), CDKL5-deficiency disorder (Orphanet:505652), Nance-Horan syndrome (Orphanet:627), X-linked non-syndromic intellectual disability (Orphanet:777), Congenital bilateral absence of vas deferens (Orphanet:48), Pyruvate dehydrogenase E1-alpha deficiency (Orphanet:79243), Isolated cerebellar agenesis (Orphanet:1398), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

10 total (12 of 10 shown, HPO-id order):

HPO	Term
HP:0000027	Azoospermia
HP:0000122	Unilateral renal agenesis
HP:0000798	Oligozoospermia
HP:0001417	X-linked inheritance
HP:0003251	Male infertility
HP:0011462	Young adult onset
HP:0011962	Obstructive azoospermia
HP:0012210	Abnormal renal morphology
HP:0012873	Absent vas deferens
HP:0430121	Seminal vesicle agenesis
HP:0000252	Microcephaly
HP:0000473	Torticollis

GWAS associations

0 associations (top):

MeSH disease descriptors (12)

Descriptor	Name	Tree numbers
D038921	Coffin-Lowry Syndrome	C10.597.606.360.455.249; C16.320.322.500.249; C16.320.400.525.249
D006015	Glycogen Storage Disease Type VIII	C16.320.322.217; C16.320.565.202.449.620; C18.452.648.202.449.620
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C564064	CDKL5 deficiency disorder (supp.)
C562568	Cerebellar Hypoplasia (supp.)
C536435	Coffin syndrome 1 (supp.)
C535425	Congenital torticollis (supp.)
C564421	Liver Glycogenosis, X-Linked, Type II (supp.)
C563141	Mental Retardation, X-Linked 19 (supp.)
C538336	Nance-Horan syndrome (supp.)
C564071	Pyruvate Dehydrogenase E1 Alpha Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523893 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Adhesion Class GPCRs

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
Nb23-bi	Positive	6.34	pKd

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases methylation	5
Valproic Acid	affects expression, decreases methylation, increases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
Cisplatin	affects expression, affects cotreatment, decreases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Tobacco Smoke Pollution	decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
titanium dioxide	decreases expression	1
butyraldehyde	decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
benzo(e)pyrene	increases methylation	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, decreases expression, affects cotreatment	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Cadmium	decreases expression	1
Doxorubicin	decreases expression	1
Folic Acid	decreases 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
CHEMBL4883463	Binding	PRESTO-Tango GPCRome screening (GPR64)	Data for DCP probe UCSF924

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04521452	PHASE4	UNKNOWN	Randomized, Open-label Trial of Inhibitory Effect of Evogliptin on Progression of CAVD
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT01384214	PHASE4	COMPLETED	Effect of Botulinum Toxin Type A on Swallowing in Patients With Cervical Dystonia
NCT02651311	PHASE4	COMPLETED	Ultrasound Guided Intermediate Cervical Plexus Block for Congenital Muscular Torticollis
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT02706795	PHASE2	COMPLETED	Dose-escalating Safety and Preliminary Efficacy of DaxibotulinumtoxinA for Injection in Cervical Dystonia
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00175604	PHASE1	WITHDRAWN	Comparative Trial of Botox in the Management of Children With Congenital Muscular Torticollis
NCT01041157	PHASE1	UNKNOWN	Botulinum Toxin Injection Efficiency
NCT06045702	Not specified	RECRUITING	Establishment of a Primary Epididymal Cell Model From Epididymal Samples to Study CFTR Gene Regulation
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02385162	Not specified	WITHDRAWN	Biomarker for Glycogen Storage Diseases (BioGlycogen)
NCT04454216	Not specified	RECRUITING	GSD VI and GSD IX Natural History
NCT05257005	Not specified	UNKNOWN	Natural History Study of Pyruvate Dehydrogenase Deficiency
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability