ADGRG1

Summary

ADGRG1 (adhesion G protein-coupled receptor G1, HGNC:4512) is a protein-coding gene on chromosome 16q21, encoding Adhesion G-protein coupled receptor G1 (Q9Y653). Adhesion G-protein coupled receptor (aGPCR) for steroid hormone 17alpha-hydroxypregnenolone (17-OH), which is involved in cell adhesion and cell-cell interactions.

This gene encodes a member of the G protein-coupled receptor family and regulates brain cortical patterning. The encoded protein binds specifically to transglutaminase 2, a component of tissue and tumor stroma implicated as an inhibitor of tumor progression. Mutations in this gene are associated with a brain malformation known as bilateral frontoparietal polymicrogyria. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 9289 — RefSeq curated summary.

At a glance

• Gene–disease (curated): bilateral frontoparietal polymicrogyria (Definitive, ClinGen)
• GWAS associations: 3
• Clinical variants (ClinVar): 1,135 total — 64 pathogenic, 46 likely-pathogenic
• Phenotypes (HPO): 79
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_201525

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4512
Approved symbol	ADGRG1
Name	adhesion G protein-coupled receptor G1
Location	16q21
Locus type	gene with protein product
Status	Approved
Aliases	TM7LN4, TM7XN1
Ensembl gene	ENSG00000205336
Ensembl biotype	protein_coding
OMIM	604110
Entrez	9289

Gene structure

Transcript identifiers

Ensembl transcripts: 121 — 104 protein_coding, 11 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay, 2 retained_intron

ENST00000388813, ENST00000456916, ENST00000540164, ENST00000561696, ENST00000561782, ENST00000561833, ENST00000561872, ENST00000561969, ENST00000561988, ENST00000562003, ENST00000562101, ENST00000562414, ENST00000562467, ENST00000562558, ENST00000562608, ENST00000562631, ENST00000562673, ENST00000562682, ENST00000562804, ENST00000563007, ENST00000563374, ENST00000563414, ENST00000563445, ENST00000563548, ENST00000563862, ENST00000564103, ENST00000564360, ENST00000564722, ENST00000564729, ENST00000564783, ENST00000564907, ENST00000564912, ENST00000565013, ENST00000565314, ENST00000565338, ENST00000565391, ENST00000565505, ENST00000565539, ENST00000565587, ENST00000565770, ENST00000565976, ENST00000566123, ENST00000566164, ENST00000566169, ENST00000566187, ENST00000566271, ENST00000566508, ENST00000566778, ENST00000566888, ENST00000567154, ENST00000567397, ENST00000567553, ENST00000567702, ENST00000567835, ENST00000567915, ENST00000568074, ENST00000568157, ENST00000568234, ENST00000568487, ENST00000568531, ENST00000568618, ENST00000568645, ENST00000568700, ENST00000568791, ENST00000568908, ENST00000568909, ENST00000568979, ENST00000569101, ENST00000569132, ENST00000569154, ENST00000569158, ENST00000569372, ENST00000569494, ENST00000569531, ENST00000569992, ENST00000570044, ENST00000672974, ENST00000673126, ENST00000678252, ENST00000860530, ENST00000860534, ENST00000860536, ENST00000860538, ENST00000860540, ENST00000860541, ENST00000860542, ENST00000860543, ENST00000860544, ENST00000860545, ENST00000860546, ENST00000860547, ENST00000860548, ENST00000860549, ENST00000860550, ENST00000860551, ENST00000860552, ENST00000860553, ENST00000860554, ENST00000860555, ENST00000860556, ENST00000860557, ENST00000860558, ENST00000860559, ENST00000860560, ENST00000860561, ENST00000860562, ENST00000860563, ENST00000860564, ENST00000923220, ENST00000972394, ENST00000972395, ENST00000972396, ENST00000972397, ENST00000972398, ENST00000972399, ENST00000972400, ENST00000972401, ENST00000972402, ENST00000972403, ENST00000972404, ENST00000972405

RefSeq mRNA: 29 — MANE Select: NM_201525 NM_001145770, NM_001145771, NM_001145772, NM_001145773, NM_001145774, NM_001290142, NM_001290143, NM_001290144, NM_001370428, NM_001370429, NM_001370430, NM_001370431, NM_001370432, NM_001370433, NM_001370434, NM_001370435, NM_001370436, NM_001370437, NM_001370438, NM_001370439, NM_001370440, NM_001370441, NM_001370442, NM_001370451, NM_001370453, NM_001370454, NM_005682, NM_201524, NM_201525

CCDS: CCDS32460, CCDS32461, CCDS73893

Canonical transcript exons

ENST00000562631 — 14 exons

Exon	Start	End
ENSE00002624164	57628630	57628802
ENSE00003469556	57655876	57655992
ENSE00003473347	57653203	57653335
ENSE00003476989	57659413	57659681
ENSE00003522134	57657373	57657491
ENSE00003603353	57661697	57661965
ENSE00003629749	57656226	57656271
ENSE00003635590	57660768	57660876
ENSE00003674202	57650253	57650351
ENSE00003679670	57656514	57656617
ENSE00003694271	57655399	57655530
ENSE00003783977	57651200	57651622
ENSE00003784613	57653986	57654133
ENSE00003891206	57663452	57665567

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 99.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 46.0807 / max 1034.9393, expressed in 1407 samples.

FANTOM5 promoters (30 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154390	16.4098	1193
154392	7.3528	1053
154395	4.1038	244
154384	4.0344	382
154385	3.6780	322
154391	2.6362	648
154408	2.0907	79
154386	1.8241	313
154389	1.0027	363
154394	0.8952	181

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.16	gold quality
ganglionic eminence	UBERON:0004023	99.11	gold quality
ventricular zone	UBERON:0003053	99.02	gold quality
type B pancreatic cell	CL:0000169	98.77	gold quality
renal medulla	UBERON:0000362	98.64	gold quality
metanephros cortex	UBERON:0010533	98.52	gold quality
right lobe of thyroid gland	UBERON:0001119	98.43	gold quality
left lobe of thyroid gland	UBERON:0001120	98.31	gold quality
thyroid gland	UBERON:0002046	98.22	gold quality
adult mammalian kidney	UBERON:0000082	98.19	gold quality
islet of Langerhans	UBERON:0000006	98.18	gold quality
parotid gland	UBERON:0001831	98.11	gold quality
upper arm skin	UBERON:0004263	97.98	gold quality
caput epididymis	UBERON:0004358	97.89	gold quality
nasal cavity epithelium	UBERON:0005384	97.79	gold quality
amygdala	UBERON:0001876	97.73	gold quality
gall bladder	UBERON:0002110	97.71	gold quality
corpus epididymis	UBERON:0004359	97.71	gold quality
nipple	UBERON:0002030	97.26	gold quality
ventral tegmental area	UBERON:0002691	97.08	gold quality
temporal lobe	UBERON:0001871	97.06	gold quality
trachea	UBERON:0003126	97.02	gold quality
CA1 field of hippocampus	UBERON:0003881	96.90	gold quality
pylorus	UBERON:0001166	96.87	gold quality
skin of abdomen	UBERON:0001416	96.83	gold quality
nucleus accumbens	UBERON:0001882	96.82	gold quality
skin of leg	UBERON:0001511	96.80	gold quality
saliva-secreting gland	UBERON:0001044	96.78	gold quality
nephron tubule	UBERON:0001231	96.70	gold quality
zone of skin	UBERON:0000014	96.49	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	294.53
E-MTAB-6701	yes	125.38
E-CURD-122	yes	50.59
E-MTAB-9467	yes	29.41
E-MTAB-8142	yes	16.07
E-MTAB-6678	yes	14.49
E-ENAD-27	no	247.83
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HNF4A, RFX1, SP1, SP3

miRNA regulators (miRDB)

55 targeting ADGRG1, 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-3064-3P	100.00	70.09	1254
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-139-5P	99.80	69.50	1399
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-12130	99.75	65.47	452
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-6808-5P	99.31	66.23	2150

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• results show that mutations in GPR56 cause a human brain cortical malformatin called bilateral frontoparietal polymicrogyria (BFPP); data suggest that GPR56 signaling plays an essential role in regional development of human cerebral cortex (PMID:15044805)
• Increased expression of GPCR56 is associated with esophageal squamous cell carcinoma (PMID:15916848)
• Results show that GPR56 binds specifically to tissue transglutaminase, TG2, a widespread component of tissue and tumor stroma previously implicated as an inhibitor of tumor progression. (PMID:16757564)
• Review describes the expression of a ligand that interacts with GPR56 in metastatic melanoma cells as TG2, a major crosslinking enzyme in the tumor extracellular matrix. (PMID:17314516)
• These results define the biochemical properties of GPR56 protein, and suggest that the expression of GPR56 protein is suppressed in human pancreatic cancer cells. (PMID:17932623)
• We have shown that GPR56 GPS mutant protein is defective in cleavage and surface localization, while non-GPS mutant proteins are cleaved normally but still defective in surface localization. (PMID:18042463)
• This study reported that three consanguineous families in which four affected individuals with Bilateral frontoparietal polymicrogyria and GPR56 mutations had Lennox-Gastaut syndrome. (PMID:19016831)
• Our data suggest that GPR56 can be used as an NSC/NPC marker within the neural cell lineage, especially in combination with nestin. (PMID:19525879)
• Results suggest that the splicing of GPR56 may induce differential tumorigenic responses owing to their varied ability to activate transcription factors. (PMID:19572147)
• Identify GPR56 as a novel marker capable of discriminating different natural killer cells subsets. (PMID:20008459)
• A significant correlation between GPR56, TG2, and NF-kappaB was observed that correlated with nodal metastasis and tumor invasion in esophageal squamous cell carcinoma. (PMID:20874003)
• GPR56 mutations cause bilateral frontoparietal polymicrogyria via multiple mechanisms (PMID:21349848)
• The N terminus of the adhesion G protein-coupled receptor GPR56 controls receptor signaling activity. (PMID:21708946)
• study reports a novel missense mutation of GPR56, E496K, identified in a consanguineous pedigree with bilateral frontoparietal polymicrogyria (PMID:21723461)
• consistent with its suppressive roles in melanoma progression, the expression levels of GPR56 are inversely correlated with the malignancy of melanomas in human subjects (PMID:21724588)
• GPR56 expression is a common trait of human cytotoxic lymphocytes and might affect the migratory properties of these cells. (PMID:21724806)
• Disease-associated mutations prevent GPR56-collagen III interaction. (PMID:22238662)
• The present study confirms the phenotypic overlap between GPR56-related brain dysgenesis and other cobblestone-like syndromes. (PMID:23274687)
• GPR56 may represent an important GPCR for the maintenance of HSCs by acting as a co-ordinator of interactions with the BM osteosteal niche. (PMID:23478665)
• GPR56, MT1G, and RASSF1 might be the potential methylation markers associated with acquired multidrug resistance of lung adenocarcinoma. (PMID:23902976)
• Loss of GPR56 is associated with abnormal muscle development. (PMID:24102982)
• these data reveal a mechanism by which control of GPR56 expression pattern by multiple alternative promoters can influence stem cell proliferation, gyral patterning, and, potentially, neocortex evolution. (PMID:24531968)
• These findings demonstrate that reduced expression of GPR56 in lung fibroblasts may be an important link with pulmonary fibrosis, playing a role in regulating some important fibroblast functions. (PMID:24742924)
• Data show that Gpr56, a G-coupled protein receptor, is required for hematopoietic cluster formation during transdifferentiation process in endothelial to hematopoietic cell transition (EHT). (PMID:25547674)
• Agonistic antibodies reveal the function of GPR56 in human glioma U87-MG cells (PMID:25832639)
• GPR56 and GPR110 are activated by exposure of a cryptic tethered agonist (PMID:25918380)
• we knocked down GPR56 in cardiomyocytes and found that GPR56 promoted Ang II-induced cardiomyocyte hypertrophy and it contributed to PCBP2 effects on cardiomyocyte hypertrophy (PMID:26116532)
• Data suggest that agonist-induced signal transduction via either GPR56/ADGRG1 or BAI1/ADGRB1 does not require conserved membrane-proximal stalk region of these proteins; ADGRG1 may participate in stalk-dependent and stalk-independent signaling. (PMID:26710850)
• High GPR56 expression was significantly associated with high-risk genetic subgroups and poor outcome in patients with acute myeloid leukemia and identifies cancer stem cells with high repopulating potential. (PMID:26834243)
• Functional relevance of GPR56 expression was validated in mice, in which co-expression of Gpr56 significantly accelerated HOXA9-induced leukemogenesis (PMID:27063597)
• GPR56 inhibits natural cytotoxicity of human NK cells. (PMID:27184850)
• GPR56 regulates the proliferation and invasion capacity of osteosarcoma cells. (PMID:27396430)
• expression and activation of GPR56 may modulate melanoma progression in part by inducing IL-6 production after N-terminal fragment dissociation and C-terminal fragment self-activation (PMID:27818281)
• GPR56 may play an oncogenic role through the Rho and E-cadherin pathway in human epithelial ovarian cancer (PMID:27881002)
• Brain MRI in the affected siblings as well as in the two previously reported individuals with bi-allelic COL3A1 mutations showed a brain phenotype similar to that associated with mutations in GPR56. (PMID:28258187)
• Disease-associated extracellular loop mutations in the adhesion G protein-coupled receptor G1 (ADGRG1; GPR56) differentially regulate downstream signaling (PMID:28424266)
• The authors conclude that soluble GPR56 is present in vivo and is elevated in certain chronic inflammatory diseases such as rheumatoid arthritis. Hence, soluble GPR56 might be considered a potential biomarker for rheumatoid arthritis disease progression. (PMID:28690029)
• We report a clinical feature, electroclinical findings, and clinical course of a patient with a severe phenotype of MCPH2 including microcephaly, refractory infantile spasms and intellectual disability. We detected a new homozygous splicing variant c.3335+1G>C in the WD repeat domain 62 (WDR62) gene, and an additional new heterozygous missense mutation c.1706T>A of G protein-coupled receptor 56 (GPR56) gene (PMID:28756000)
• Stachel-independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region. (PMID:28874577)
• that GPR56 might be an inhibitor of the mesenchymal transition across multiple tumor types beyond glioblastoma (PMID:29166609)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Adgrg1	ENSMUSG00000031785
rattus_norvegicus	Adgrg1	ENSRNOG00000014963

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), ADGRG2 (ENSG00000173698), ADGRE1 (ENSG00000174837), ADGRD2 (ENSG00000180264), ADGRB1 (ENSG00000181790), ADGRG3 (ENSG00000182885)

Protein

Protein identifiers

Adhesion G-protein coupled receptor G1 — Q9Y653 (reviewed: Q9Y653)

Alternative names: G-protein coupled receptor 56

All UniProt accessions (51): Q9Y653, A0A024R6U7, A0A0S2Z517, A0A1B0GX62, A0A5F9ZH94, A0A5F9ZHT7, H3BM73, H3BMC2, H3BMF8, H3BMY9, H3BNH4, H3BNN3, H3BP67, H3BP94, H3BPA6, H3BPC0, H3BQ11, H3BQ46, H3BQJ9, H3BQW4, H3BQZ1, H3BRA1, H3BRB4, H3BRH0, H3BRI2, H3BRI7, H3BRZ4, H3BS14, H3BS54, H3BS94, H3BS98, H3BSB8, H3BSF7, H3BSJ6, H3BSN3, H3BSN7, H3BSP5, H3BSR1, H3BT88, H3BTD2, H3BTH7, H3BTK9, H3BUF5, H3BUH2, H3BUU6, H3BV52, H3BV72, H3BV84, H3BVA0, H3BVD3, H3BVE9

UniProt curated annotations — full annotation on UniProt →

Function. Adhesion G-protein coupled receptor (aGPCR) for steroid hormone 17alpha-hydroxypregnenolone (17-OH), which is involved in cell adhesion and cell-cell interactions. 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 RhoA pathway. ADGRG1 is coupled to G(12) and/or G(13) G proteins (GNA12 and GNA13, respectively) and mediates the activation Rho small GTPases. Acts as a potent suppressor of ferroptosis: binding to 17-OH-binding initiates signaling that down-regulates CD36 and alleviates ferroptosis-induced liver injury. Ligand-binding also induces cell adhesion activity via association with proteins such as collagen III/COL3A1 and TGM2. Mediates cell matrix adhesion in developing neurons and hematopoietic stem cells. Involved in cortical development, specifically in maintenance of the pial basement membrane integrity and in cortical lamination: association with COL3A1 in the developing brain inhibits neuronal migration via activation of the RhoA pathway. Together with TGM2, acts as a regulator of myelination and myelin repair in oligodendrocyte precursor cells. Acts as a hemostatic sensor of shear force: G protein-coupled receptor signaling is activated in response to shear force in platelets, promoting G(13) G protein signaling, and platelet shape change and aggregation in a COL3A1-dependent manner. Acts as an inhibitor of VEGFA production thereby inhibiting angiogenesis through a signaling pathway mediated by PRKCA. Plays a role in the maintenance of hematopoietic stem cells in bone marrow niche. Plays an essential role in testis development.

Subunit / interactions. Heterodimer of 2 chains generated by proteolytic processing; the large extracellular N-terminal fragment (ADGRG1 NT) and the membrane-bound C-terminal fragment (ADGRG1-CT) predominantly remain associated and non-covalently linked. ADGRG1 NT self-associates in a trans-trans manner; the homophilic interaction enhances receptor signaling. Interacts with TGM2. Interacts with heparin; leading to the reduction of ADGRG1 shedding. Interacts with COL3A1. Part of a GPCR-tetraspanin complex at least consisting of ADGRG1, CD81, eventually CD9, and GNA11 in which CD81 is enhancing the association of ADGRG1 with GNA11.

Subcellular location. Cell membrane Secreted Membrane raft.

Tissue specificity. Widely distributed with highest levels found in thyroid gland, brain and heart. Expressed in a great number of tumor cells. Expression is down-regulated in different tumors from highly metastatic cells.

Post-translational modifications. Autoproteolytically cleaved into 2 fragments; the large extracellular N-terminal fragment (ADGRG1 NT) and the membrane-bound C-terminal fragment (ADGRG1 CT) predominantly remain associated and non-covalently linked. Shedding to yield the secreted ADGRG1 N-terminal fragment seems to involve metalloprotease(s). N-glycosylated. Contains sialic acid residues. Ubiquitinated. Undergoes polyubiquitination upon activation.

Disease relevance. Cortical dysplasia, complex, with other brain malformations 14A (bilateral frontoparietal) (CDCBM14A) [MIM:606854] An autosomal recessive disorder characterized by global developmental delay with impaired intellectual development, motor delay, poor speech, cerebellar and pyramidal signs, truncal ataxia, and early-onset seizures. Brain imaging shows bilateral frontoparietal polymicrogyria, a malformation of the cortex in which the brain surface is irregular and characterized by an excessive number of small gyri with abnormal lamination. Polymicrogyria is considered to be the result of postmigratory abnormal cortical organization. The disease is caused by variants affecting the gene represented in this entry. Cortical dysplasia, complex, with other brain malformations 14B (bilateral perisylvian) (CDCBM14B) [MIM:615752] An autosomal recessive disorder characterized by strikingly restricted polymicrogyria limited to the cortex surrounding the Sylvian fissure. Affected individuals have intellectual and language difficulty and seizures, but no motor disability. Polymicrogyria is a malformation of the cortex in which the brain surface is irregular and characterized by an excessive number of small gyri with abnormal lamination. It is considered to be the result of postmigratory abnormal cortical organization. The disease is caused by variants affecting the gene represented in this entry. Homozygous deletion of 1 of 2 tandem 15-bp repeats located 144 bp upstream of the ADGRG1 non-coding exon 1m transcription start site, results in impaired perisylvian ADGRG1 expression and disruption of perisylvian gyri.

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.

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.

Miscellaneous. Plays a critical role in cancer progression by inhibiting VEGFA production thereby inhibiting angiogenesis through a signaling pathway mediated by PRKCA. Has no predictable signal peptide.

Similarity. Belongs to the G-protein coupled receptor 2 family. LN-TM7 subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9Y653-1	1	yes
Q9Y653-2	2, S1
Q9Y653-3	3, S2
Q9Y653-4	4, S3
Q9Y653-5	5, S4

RefSeq proteins (29): NP_001139242, NP_001139243, NP_001139244, NP_001139245, NP_001139246, NP_001277071, NP_001277072, NP_001277073, NP_001357357, NP_001357358, NP_001357359, NP_001357360, NP_001357361, NP_001357362, NP_001357363, NP_001357364, NP_001357365, NP_001357366, NP_001357367, NP_001357368, NP_001357369, NP_001357370, NP_001357371, NP_001357380, NP_001357382, NP_001357383, NP_005673, NP_958932, NP_958933* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000203	GPS	Conserved_site
IPR000832	GPCR_2_secretin-like	Family
IPR003910	GPR1/GPR3/GPR5	Family
IPR017981	GPCR_2-like_7TM	Domain
IPR040679	PLL	Domain
IPR040950	ADGRG1_GAIN_A	Domain
IPR046338	GAIN_dom_sf	Homologous_superfamily
IPR057244	GAIN_B	Domain

Pfam: PF00002, PF01825, PF18587, PF18619

UniProt features (98 total): sequence variant 18, mutagenesis site 18, helix 12, topological domain 8, transmembrane region 7, glycosylation site 7, disulfide bond 5, splice variant 4, chain 3, region of interest 3, sequence conflict 3, binding site 2, strand 2, turn 2, signal peptide 1, domain 1, compositionally biased region 1, site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7SF8	ELECTRON MICROSCOPY	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y653-F1	78.29	0.27

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): 382–383 (cleavage; by autolysis)

Ligand- & substrate-binding residues (2): 26–33; 190–200

Disulfide bonds (5): 35–91, 121–177, 346–377, 366–379, 475–562

Glycosylation sites (7): 39, 148, 171, 234, 303, 324, 341

Mutagenesis-validated functional residues (18):

Position	Phenotype
28	abolishes heparin-binding; when associated with a-29 and a-33.
29	abolishes heparin-binding; when associated with a-28 and a-33.
33	reduces heparin-binding. abolishes heparin-binding; when associated with a-28 and a-29.
381	abolishes cleavage.
383	abolishes cleavage but does not affect cell membrane localization or signaling activity.
384	strongly decreased g protein-coupled receptor activity.
385	strongly decreased g protein-coupled receptor activity.
386	impaired g protein-coupled receptor activity.
389	abolished g protein-coupled receptor activity.
454	strongly decreased g protein-coupled receptor activity.
482	impaired g protein-coupled receptor activity in response to 17alpha-hydroxypregnenolone-binding.
486	impaired g protein-coupled receptor activity in response to 17alpha-hydroxypregnenolone-binding.
563	impaired g protein-coupled receptor activity in response to 17alpha-hydroxypregnenolone-binding.
570	impaired g protein-coupled receptor activity in response to 17alpha-hydroxypregnenolone-binding.
571	impaired g protein-coupled receptor activity in response to 17alpha-hydroxypregnenolone-binding.
574	impaired g protein-coupled receptor activity in response to 17alpha-hydroxypregnenolone-binding.
623	impaired g protein-coupled receptor activity in response to 17alpha-hydroxypregnenolone-binding.
643	impaired g protein-coupled receptor activity in response to 17alpha-hydroxypregnenolone-binding.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 480 (showing top): VALK_AML_WITH_FLT3_ITD, GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, ELVIDGE_HYPOXIA_DN, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_SIGNALING_PATHWAY, GOBP_PLATELET_ACTIVATION, GOZGIT_ESR1_TARGETS_DN, GOBP_POSITIVE_REGULATION_OF_RHO_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_LAYER_FORMATION_IN_CEREBRAL_CORTEX, GOBP_NEUROGENESIS, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_CELL_CELL_SIGNALING, GOBP_FOREBRAIN_REGIONALIZATION

GO Biological Process (31): angiogenesis (GO:0001525), cell adhesion (GO:0007155), cell surface receptor signaling pathway (GO:0007166), G protein-coupled receptor signaling pathway (GO:0007186), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), Rho protein signal transduction (GO:0007266), cell-cell signaling (GO:0007267), brain development (GO:0007420), negative regulation of cell population proliferation (GO:0008285), cell migration (GO:0016477), cerebral cortex regionalization (GO:0021796), cerebral cortex radial glia-guided migration (GO:0021801), layer formation in cerebral cortex (GO:0021819), positive regulation of Rho protein signal transduction (GO:0035025), positive regulation of cell adhesion (GO:0045785), neural precursor cell proliferation (GO:0061351), hematopoietic stem cell homeostasis (GO:0061484), seminiferous tubule development (GO:0072520), regulation of platelet aggregation (GO:0090330), negative regulation of ferroptosis (GO:0110076), Rho-activating G protein-coupled receptor signaling pathway (GO:0160221), positive regulation of vascular endothelial growth factor signaling pathway (GO:1900748), positive regulation of neural precursor cell proliferation (GO:2000179), negative regulation of neuron migration (GO:2001223), signal transduction (GO:0007165), nervous system development (GO:0007399), positive regulation of signal transduction (GO:0009967), cell differentiation (GO:0030154), tube development (GO:0035295), regulation of cell population proliferation (GO:0042127), anatomical structure formation involved in morphogenesis (GO:0048646)

GO Molecular Function (6): G protein-coupled receptor activity (GO:0004930), collagen binding (GO:0005518), heparin binding (GO:0008201), extracellular matrix binding (GO:0050840), transmembrane signaling receptor activity (GO:0004888), protein binding (GO:0005515)

GO Cellular Component (6): plasma membrane (GO:0005886), membrane (GO:0016020), membrane raft (GO:0045121), extracellular exosome (GO:0070062), glial limiting end-foot (GO:0097451), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure formation involved in morphogenesis	2
signal transduction	2
G protein-coupled receptor signaling pathway	2
cell population proliferation	2
binding	2
cellular anatomical structure	2
blood vessel morphogenesis	1
cellular process	1
G protein-coupled receptor activity	1
phospholipase C activator activity	1
small GTPase-mediated signal transduction	1
cell communication	1
signaling	1
central nervous system development	1
animal organ development	1
head development	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
cell motility	1
regionalization	1
telencephalon regionalization	1
cerebral cortex development	1
cerebral cortex radially oriented cell migration	1
telencephalon glial cell migration	1
cerebral cortex radial glia-guided migration	1
Rho protein signal transduction	1
regulation of Rho protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
cell adhesion	1
regulation of cell adhesion	1
positive regulation of cellular process	1
homeostasis of number of cells	1
male gonad development	1
tube development	1
reproductive structure development	1
regulation of platelet activation	1
regulation of homotypic cell-cell adhesion	1
platelet aggregation	1
negative regulation of programmed cell death	1
ferroptosis	1

Protein interactions and networks

STRING

1284 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADGRG1	GNA12	Q03113	952
ADGRG1	TGM2	P21980	849
ADGRG1	GNAQ	P50148	743
ADGRG1	CD9	P21926	714
ADGRG1	COL3A1	P02461	694
ADGRG1	SCT	P09683	652
ADGRG1	TBL2	Q9Y4P3	636
ADGRG1	SCTR	P47872	592
ADGRG1	FN1	P02751	589
ADGRG1	EIF4H	Q15056	585
ADGRG1	FZD9	O00144	582
ADGRG1	CD81	P18582	580
ADGRG1	NSUN5	Q96P11	580
ADGRG1	BCL7B	Q9BQE9	580
ADGRG1	ADGRA1	Q86SQ6	559

IntAct

192 interactions, top by confidence:

A	B	Type	Score
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
FPR2	ARL6IP5	psi-mi:“MI:0914”(association)	0.640
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
CTLA4	B4GALT5	psi-mi:“MI:0914”(association)	0.530
SLC30A2	ESYT2	psi-mi:“MI:0914”(association)	0.530
TMEM184A	SLC33A1	psi-mi:“MI:0914”(association)	0.530
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
Col3a1	ADGRG1	psi-mi:“MI:0403”(colocalization)	0.490
Col3a1	ADGRG1	psi-mi:“MI:0407”(direct interaction)	0.490
ADGRG1	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRG1	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRG1	SHANK1	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRG1	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRG1	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRG1	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRG1	ARHGEF12	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRG1	GRID2IP	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRG1	GOPC	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRG1	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
WHRN	ADGRG1	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRG1	PARD3B	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRG1	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRG1	RHPN1	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	ADGRG1	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRG1	MPP2	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRG1	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRG1	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRG1	LIN7C	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (65): GPR56 (Synthetic Lethality), GPR56 (Affinity Capture-RNA), GPR56 (Affinity Capture-MS), GPR56 (Proximity Label-MS), GPR56 (Proximity Label-MS), GPR56 (Affinity Capture-MS), GPR56 (Two-hybrid), GPR56 (Two-hybrid), GPR56 (Affinity Capture-MS), GPR56 (Affinity Capture-MS), GPR56 (Affinity Capture-MS), GPR56 (Affinity Capture-MS), GPR56 (Affinity Capture-MS), GPR56 (Affinity Capture-MS), GPR56 (Affinity Capture-MS)

ESM2 similar proteins: E7FBY6, O35674, O43184, P11688, P21463, P47750, P48960, P56495, Q06418, Q14246, Q27987, Q2Q421, Q2Q426, Q3V3Z3, Q49HI0, Q50DM5, Q50DM6, Q50DM7, Q50DM8, Q5SZV5, Q5Y4N8, Q61549, Q61824, Q6F3F9, Q7RTX1, Q7Z443, Q86Y34, Q8CJ11, Q8CJ12, Q8IZF5, Q8IZP9, Q8K209, Q8K3V3, Q8R0T6, Q8SPP9, Q8SQA4, Q90674, Q91ZE5, Q91ZV8, Q923K1

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

5 interactions.

A	Effect	B	Mechanism
ADGRG1	“up-regulates activity”	GNA12	binding
ADGRG1	“up-regulates activity”	GNA13	binding
COL3A1	“up-regulates activity”	ADGRG1	binding
ADGRG1	“up-regulates activity”	ADGRG1	cleavage
ADGRG1	“up-regulates activity”	RHOA	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 182 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Assembly and cell surface presentation of NMDA receptors	7	15.2×	8e-05
Protein-protein interactions at synapses	6	13.6×	7e-04
Neurexins and neuroligins	8	13.5×	6e-05

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	31.3×	7e-09
receptor clustering	6	22.4×	9e-05
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	6	7.9×	9e-03
protein-containing complex assembly	10	6.8×	5e-04
positive regulation of cytosolic calcium ion concentration	8	5.6×	9e-03
cell-cell adhesion	9	5.5×	6e-03
cell adhesion	16	3.6×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1135 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	64
Likely pathogenic	46
Uncertain significance	285
Likely benign	533
Benign	81

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068553	NM_201525.4(ADGRG1):c.900+1del	Pathogenic
1074225	NM_201525.4(ADGRG1):c.1553G>A (p.Trp518Ter)	Pathogenic
1369485	NM_201525.4(ADGRG1):c.1486C>T (p.Arg496Ter)	Pathogenic
1403351	NM_201525.4(ADGRG1):c.37del (p.Leu13fs)	Pathogenic
1406793	NM_201525.4(ADGRG1):c.1900del (p.Leu634fs)	Pathogenic
1452354	NM_201525.4(ADGRG1):c.739C>T (p.Gln247Ter)	Pathogenic
1453100	NM_201525.4(ADGRG1):c.429dup (p.Trp144fs)	Pathogenic
1455281	NC_000016.9:g.(?57684190)(57685544_?)del	Pathogenic
1456486	NM_201525.4(ADGRG1):c.1888C>T (p.Gln630Ter)	Pathogenic
1458590	NM_201525.4(ADGRG1):c.1006C>T (p.Gln336Ter)	Pathogenic
1460403	NM_201525.4(ADGRG1):c.1327del (p.Leu443fs)	Pathogenic
158618	NM_201525.4(ADGRG1):c.1408C>T (p.Arg470Ter)	Pathogenic
158621	NM_201525.4(ADGRG1):c.1515T>G (p.Tyr505Ter)	Pathogenic
158628	NM_201525.4(ADGRG1):c.265C>T (p.His89Tyr)	Pathogenic
1694450	NM_201525.4(ADGRG1):c.580C>T (p.Gln194Ter)	Pathogenic
1701031	NM_201525.4(ADGRG1):c.619_620+2del	Pathogenic
1924588	NM_201525.4(ADGRG1):c.203_206dup (p.Pro70fs)	Pathogenic
1974309	NM_201525.4(ADGRG1):c.279C>A (p.Tyr93Ter)	Pathogenic
2023989	NM_201525.4(ADGRG1):c.812del (p.Arg271fs)	Pathogenic
2028121	NM_201525.4(ADGRG1):c.772G>T (p.Glu258Ter)	Pathogenic
2094569	NM_201525.4(ADGRG1):c.896dup (p.Gln300fs)	Pathogenic
2107261	NM_201525.4(ADGRG1):c.874del (p.Asp292fs)	Pathogenic
211093	NM_201525.4(ADGRG1):c.1216del (p.Leu406fs)	Pathogenic
211096	NM_201525.4(ADGRG1):c.944_945dup (p.Val316fs)	Pathogenic
2137834	NM_201525.4(ADGRG1):c.105C>A (p.Cys35Ter)	Pathogenic
2426640	NC_000016.9:g.(?56226148)(58768132_?)del	Pathogenic
2426846	NC_000016.9:g.(?57016057)(58768132_?)del	Pathogenic
2579668	NM_201525.4(ADGRG1):c.209C>T (p.Pro70Leu)	Pathogenic
2705696	NM_201525.4(ADGRG1):c.193del (p.Leu65fs)	Pathogenic
2707147	NM_201525.4(ADGRG1):c.315T>G (p.Tyr105Ter)	Pathogenic

SpliceAI

2640 predictions. Top by Δscore:

Variant	Effect	Δscore
16:57650247:TTCCA:T	acceptor_loss	1.0000
16:57650248:TCCA:T	acceptor_loss	1.0000
16:57650249:CCA:C	acceptor_loss	1.0000
16:57650251:A:AC	acceptor_loss	1.0000
16:57650252:GGT:G	acceptor_gain	1.0000
16:57650326:GC:G	donor_gain	1.0000
16:57650327:C:G	donor_gain	1.0000
16:57651623:G:GG	donor_gain	1.0000
16:57653332:GCCA:G	donor_gain	1.0000
16:57653333:CCA:C	donor_gain	1.0000
16:57653335:AG:A	donor_loss	1.0000
16:57653336:G:GG	donor_gain	1.0000
16:57653981:GCCAG:G	acceptor_loss	1.0000
16:57653983:CA:C	acceptor_loss	1.0000
16:57653985:GGCA:G	acceptor_gain	1.0000
16:57654079:G:GT	donor_gain	1.0000
16:57654107:G:GT	donor_gain	1.0000
16:57654128:C:T	donor_gain	1.0000
16:57654131:G:GT	donor_gain	1.0000
16:57654155:G:GT	donor_gain	1.0000
16:57655397:A:AG	acceptor_gain	1.0000
16:57655397:A:T	acceptor_loss	1.0000
16:57655398:G:GG	acceptor_gain	1.0000
16:57655398:GGA:G	acceptor_gain	1.0000
16:57655526:TCCAG:T	donor_loss	1.0000
16:57655527:CCAGG:C	donor_loss	1.0000
16:57655528:CAGG:C	donor_loss	1.0000
16:57655529:AGGTA:A	donor_loss	1.0000
16:57655530:GGTAT:G	donor_loss	1.0000
16:57655531:G:T	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000011435 (16:57660127 A>G,T), RS1000056356 (16:57623915 T>C), RS1000122903 (16:57664604 T>C), RS1000153912 (16:57664396 C>G,T), RS1000294006 (16:57619190 A>G,T), RS1000355747 (16:57633227 C>A,T), RS1000421403 (16:57639432 C>T), RS1000532845 (16:57645204 G>A,C), RS1000626188 (16:57629046 G>C,T), RS1000834885 (16:57656124 G>A,T), RS1000918064 (16:57639211 G>A), RS1000948959 (16:57655903 G>A), RS1000961889 (16:57619754 T>A), RS1001051653 (16:57661186 T>A), RS1001167608 (16:57659898 C>T)

Disease associations

OMIM: gene MIM:604110 | disease phenotypes: MIM:606854, MIM:615752, MIM:209900, MIM:117000

GenCC curated gene-disease

Disease	Classification	Inheritance
bilateral frontoparietal polymicrogyria	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
bilateral frontoparietal polymicrogyria	Definitive	AR

Mondo (7): bilateral frontoparietal polymicrogyria (MONDO:0011738), polymicrogyria, bilateral perisylvian, autosomal recessive (MONDO:0014333), Bardet-Biedl syndrome (MONDO:0015229), developmental and epileptic encephalopathy (MONDO:0100620), congenital myopathy (MONDO:0019952), strabismus (MONDO:0003432), congenital nervous system disorder (MONDO:0002320)

Orphanet (3): Bilateral frontoparietal polymicrogyria (Orphanet:101070), Bardet-Biedl syndrome (Orphanet:110), Congenital myopathy (Orphanet:97245)

HPO phenotypes

79 total (30 of 79 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000453	Choanal atresia
HP:0000486	Strabismus
HP:0000565	Esotropia
HP:0000577	Exotropia
HP:0000639	Nystagmus
HP:0000750	Delayed speech and language development
HP:0000767	Pectus excavatum
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001276	Hypertonia
HP:0001310	Dysmetria
HP:0001317	Abnormal cerebellum morphology
HP:0001320	Cerebellar vermis hypoplasia
HP:0001321	Cerebellar hypoplasia
HP:0001328	Specific learning disability
HP:0001347	Hyperreflexia
HP:0001349	Facial diplegia
HP:0001371	Flexion contracture
HP:0001511	Intrauterine growth retardation
HP:0001999	Abnormal facial shape
HP:0002015	Dysphagia
HP:0002020	Gastroesophageal reflux

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006083_10	Prostate cancer (advanced)	7.000000e-07
GCST006085_89	Prostate cancer	2.000000e-11
GCST010242_188	HDL cholesterol levels	5.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D020788	Bardet-Biedl Syndrome	C10.228.140.617.200; C11.270.684.624; C16.131.077.245.125; C16.320.184.125
D013285	Strabismus	C10.292.562.887; C11.590.810
C564652	Polymicrogyria, Bilateral Frontoparietal (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4523929 (SINGLE PROTEIN), CHEMBL4742327 (PROTEIN-PROTEIN INTERACTION)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Adhesion Class GPCRs

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	7
Aflatoxin B1	increases methylation, affects expression, increases expression	7
sodium arsenite	decreases methylation, affects cotreatment, decreases expression, increases abundance, increases expression	5
bisphenol A	decreases methylation, increases expression	3
lasiocarpine	increases expression	2
methyleugenol	increases expression	2
perfluorooctane sulfonic acid	increases expression	2
entinostat	decreases expression, affects cotreatment	2
belinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Acetaminophen	increases expression	2
Arsenic	increases abundance, affects expression, affects cotreatment, decreases expression	2
Cisplatin	affects expression, affects cotreatment, decreases expression	2
Estradiol	affects expression, increases expression	2
N-Nitrosopyrrolidine	increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Silicon Dioxide	decreases expression	2
Tretinoin	decreases expression	2
Valproic Acid	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	2
Cyclosporine	increases expression, affects cotreatment	2
Acrylamide	decreases expression	2
Particulate Matter	affects cotreatment, increases abundance, increases expression, affects expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
FR900359	decreases phosphorylation	1
sotorasib	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4883458	Binding	PRESTO-Tango GPCRome screening (GPR56)	Data for DCP probe UCSF924

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B9WB	Abcam THP-1 ADGRG1 KO	Cancer cell line	Male
CVCL_C6YC	Abcam PC-3 ADGRG1 KO	Cancer cell line	Male
CVCL_VE75	PFIZi023-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00461656	PHASE4	COMPLETED	Povidone-iodine Antisepsis for Strabismus Surgery
NCT01901588	PHASE4	COMPLETED	Efficacy of Single-Shot Dexmedetomidine Versus Placebo in Preventing Pediatric Emergence Delirium in Strabismus Surgery
NCT02379546	PHASE4	COMPLETED	The Effect of Anaesthesia Depth on Oculo-cardiac Reflex
NCT03349515	PHASE4	COMPLETED	The Effect of Povidone-iodine Ophthalmic Surgical Prep Solution on Respiration in Children Undergoing Strabismus Surgery With General Anesthesia.
NCT04549844	PHASE4	UNKNOWN	Peribulbar Block for Prevention of Oculocardiac Reflex
NCT06035757	PHASE4	RECRUITING	The Occurrence of Emergence Agitation in Pediatric Strabismus Surgery
NCT06560268	PHASE4	NOT_YET_RECRUITING	Low Flow Anesthesia in Children Undergoing Strabismus Surgery
NCT03746522	PHASE3	COMPLETED	Setmelanotide (RM-493), Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Participants With Moderate to Severe Obesity
NCT04966741	PHASE3	COMPLETED	Setmelanotide in Pediatric Participants With Rare Genetic Diseases of Obesity
NCT05194124	PHASE3	COMPLETED	Phase 3 Crossover Trial of Two Formulations of Setmelanotide in Participants With Specific Gene Defects in the MC4R Pathway
NCT03347526	PHASE3	SUSPENDED	A Novel Approach to Infantile Spasms
NCT03421496	PHASE3	TERMINATED	A Study to Assess Cannabidiol Oral Solution With Vigabatrin as Initial Therapy in Participants With Infantile Spasms
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT00000128	PHASE3	UNKNOWN	A Trial of Bifocals in Myopic Children With Esophoria
NCT00001864	PHASE3	COMPLETED	Amblyopia (Lazy Eye) Treatment Study
NCT00038753	PHASE3	UNKNOWN	Vision In Preschoolers Study (VIP Study)
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NCT04060771	PHASE3	UNKNOWN	Post-Operative Nausea and Vomiting in Children Submitted to Strabismus Surgery
NCT06863675	PHASE3	NOT_YET_RECRUITING	Highly Aspherical Lenslet (HAL) and Binocular Vision (BV) Disorders [HALT X(T) Study]
NCT03490019	PHASE2	WITHDRAWN	Treatment of Bardet-Biedl-Syndrome With Metformin for Evaluation of a Possible Visual Improvement
NCT04289467	PHASE2	RECRUITING	Treatment of Refractory Infantile Spasms With Fenfluramine
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NCT00478907	PHASE2	COMPLETED	Prevention of Complications of Eye Surgery
NCT06689943	PHASE2	NOT_YET_RECRUITING	Pain After Strabismus Surgery
NCT04727970	PHASE1	COMPLETED	Tricaprilin Infantile Spasms Pilot Study
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT00917982	PHASE1	UNKNOWN	The Effect of Vision Therapy/Orthoptic on Motor & Sensory Status of the 3 to 7 Years Old Strabismic Patients
NCT02246556	PHASE1	TERMINATED	Dichoptic Virtual Reality Therapy for Amblyopia in Adults
NCT00078091	Not specified	TERMINATED	Genetics and Clinical Characteristics of Bardet-Biedl Syndrome
NCT00213811	Not specified	COMPLETED	Bardet-Biedl Syndrome Study: Clinical and Genetic Epidemiology Study in Adults
NCT01401998	Not specified	RECRUITING	ARPKD Database Study
NCT02329210	Not specified	RECRUITING	Clinical Registry Investigating Bardet-Biedl Syndrome
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT04461444	Not specified	RECRUITING	COhort for Bardet-Bield Syndrome and Alström Syndrome for Translational Research Monocentric Interventional Study
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)
NCT05183802	Not specified	APPROVED_FOR_MARKETING	An Expanded Access Protocol for Setmelanotide for Treatment of Bardet-Biedl Syndrome (BBS)
NCT05400278	Not specified	COMPLETED	Characterizing the Genotype and Phenotype in Adults With Bardet-Biedl Syndrome
NCT06239064	Not specified	ACTIVE_NOT_RECRUITING	Early Genetic Identification of Obesity