ADGRF4

Summary

ADGRF4 (adhesion G protein-coupled receptor F4, HGNC:19011) is a protein-coding gene on chromosome 6p12.3, encoding Adhesion G protein-coupled receptor F4 (Q8IZF3). Orphan receptor.

Sequence analysis of this gene suggests that it is encodes a member of the superfamily of G protein-couple receptors. G protein-coupled receptors typically contain seven hydrophobic transmembrane domains, interact with guanine nucleotide binding regulatory proteins, and detect molecules outside the cell and act to transduce these signals into intracellular responses. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 221393 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 102 total
• Druggable target: yes
• MANE Select transcript: NM_153838

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19011
Approved symbol	ADGRF4
Name	adhesion G protein-coupled receptor F4
Location	6p12.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ38076, PGR18
Ensembl gene	ENSG00000153294
Ensembl biotype	protein_coding
OMIM	614268
Entrez	221393

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000283303, ENST00000327753, ENST00000371220, ENST00000863460, ENST00000863461, ENST00000959108

RefSeq mRNA: 2 — MANE Select: NM_153838 NM_001347855, NM_153838

CCDS: CCDS4922

Canonical transcript exons

ENST00000283303 — 10 exons

Exon	Start	End
ENSE00001010052	47713798	47715177
ENSE00001010057	47708224	47708278
ENSE00001010061	47712357	47712608
ENSE00001010063	47710735	47710886
ENSE00001218212	47717292	47717351
ENSE00001317867	47707230	47707338
ENSE00001454664	47718389	47718445
ENSE00001516274	47698580	47698794
ENSE00002440066	47716806	47716847
ENSE00003897012	47721209	47722014

Expression profiles

Bgee: expression breadth ubiquitous, 131 present calls, max score 90.90.

FANTOM5 (CAGE): breadth broad, TPM avg 1.7681 / max 77.6997, expressed in 377 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
68171	0.9905	311
68173	0.4692	206
68170	0.1877	121
68172	0.1206	69

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of abdomen	UBERON:0001416	90.90	gold quality
skin of leg	UBERON:0001511	90.39	gold quality
zone of skin	UBERON:0000014	88.65	gold quality
lower esophagus mucosa	UBERON:0035834	85.17	gold quality
esophagus mucosa	UBERON:0002469	85.16	gold quality
upper arm skin	UBERON:0004263	85.09	silver quality
gingival epithelium	UBERON:0001949	81.14	gold quality
penis	UBERON:0000989	80.50	gold quality
esophagus squamous epithelium	UBERON:0006920	79.17	gold quality
gingiva	UBERON:0001828	76.92	gold quality
right uterine tube	UBERON:0001302	75.78	gold quality
amniotic fluid	UBERON:0000173	75.13	gold quality
upper leg skin	UBERON:0004262	73.28	gold quality
vagina	UBERON:0000996	73.08	gold quality
oral cavity	UBERON:0000167	69.44	gold quality
skin of hip	UBERON:0001554	68.42	gold quality
esophagus	UBERON:0001043	66.68	gold quality
stromal cell of endometrium	CL:0002255	65.77	gold quality
mammalian vulva	UBERON:0000997	65.60	silver quality
islet of Langerhans	UBERON:0000006	64.99	gold quality
rectum	UBERON:0001052	64.09	gold quality
palpebral conjunctiva	UBERON:0001812	63.36	gold quality
nipple	UBERON:0002030	59.30	gold quality
gall bladder	UBERON:0002110	59.21	gold quality
urinary bladder	UBERON:0001255	58.58	gold quality
left adrenal gland	UBERON:0001234	57.52	gold quality
tonsil	UBERON:0002372	57.33	gold quality
pharyngeal mucosa	UBERON:0000355	56.03	silver quality
pancreatic ductal cell	CL:0002079	55.86	silver quality
left adrenal gland cortex	UBERON:0035825	55.86	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.70

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

30 targeting ADGRF4, 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-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-4757-5P	99.12	64.51	981
HSA-MIR-371A-5P	99.08	66.51	1914
HSA-MIR-143-5P	98.98	68.87	946
HSA-MIR-5197-3P	98.71	67.05	1905
HSA-MIR-9903	98.47	66.70	748
HSA-MIR-615-5P	98.10	63.76	591
HSA-MIR-6730-5P	98.03	68.12	1299
HSA-MIR-6883-3P	97.97	67.35	643
HSA-MIR-3664-3P	97.85	67.62	1452
HSA-MIR-4448	97.04	66.22	752
HSA-MIR-34A-3P	96.80	67.70	805
HSA-MIR-454-5P	96.51	68.35	263
HSA-MIR-5195-5P	90.84	65.09	287

Literature-anchored findings (GeneRIF, showing 1)

• Clinical significance and functional role of adhesion G-protein-coupled receptors in human pancreatic ductal adenocarcinoma. (PMID:36396823)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Adgrf4	ENSMUSG00000023918
rattus_norvegicus	Adgrf4	ENSRNOG00000012535

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), ADGRG4 (ENSG00000156920), ADGRG5 (ENSG00000159618), PTH1R (ENSG00000160801), ADGRL4 (ENSG00000162618), EVA1C (ENSG00000166979), ADGRF3 (ENSG00000173567), ADGRG2 (ENSG00000173698), ADGRE1 (ENSG00000174837), ADGRD2 (ENSG00000180264), ADGRB1 (ENSG00000181790), ADGRG3 (ENSG00000182885), ADGRA1 (ENSG00000197177)

Protein

Protein identifiers

Adhesion G protein-coupled receptor F4 — Q8IZF3 (reviewed: Q8IZF3)

Alternative names: G-protein coupled receptor 115, G-protein coupled receptor PGR18

All UniProt accessions (2): Q8IZF3, A0A0C4DFV3

UniProt curated annotations — full annotation on UniProt →

Function. Orphan receptor.

Subcellular location. Membrane.

Miscellaneous. Most adhesion GPCRs undergo autoproteolysis at the GPS region of the GAIN-B domain. ADGRF2 is not autoproteolyzed at the GPS region because of the lack of a consensus catalytic triad sequence within the GAIN-B domain.

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

RefSeq proteins (2): NP_001334784, NP_722580* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000203	GPS	Conserved_site
IPR000832	GPCR_2_secretin-like	Family
IPR008078	GPCR_2_Ig-hepta-like_rcpt	Family
IPR017981	GPCR_2-like_7TM	Domain
IPR046338	GAIN_dom_sf	Homologous_superfamily
IPR051587	Adhesion_GPCR	Family
IPR057244	GAIN_B	Domain

Pfam: PF00002, PF01825

UniProt features (41 total): glycosylation site 13, topological domain 8, transmembrane region 7, sequence variant 3, region of interest 2, disulfide bond 2, sequence conflict 2, signal peptide 1, chain 1, domain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IZF3-F1	78.70	0.39

Functional residue map

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

Disulfide bonds (2): 349–376, 364–378

Glycosylation sites (13): 61, 169, 177, 209, 229, 250, 257, 263, 264, 286, 309, 340, 379

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 47 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GSE45365_NK_CELL_VS_CD8_TCELL_DN, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOZGIT_ESR1_TARGETS_DN, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, chr6p12, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, AACTTT_UNKNOWN, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, RICKMAN_HEAD_AND_NECK_CANCER_C, GOBP_ADENYLATE_CYCLASE_ACTIVATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GOMF_G_PROTEIN_COUPLED_RECEPTOR_ACTIVITY, DUTERTRE_ESTRADIOL_RESPONSE_24HR_DN

GO Biological Process (4): 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), 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 (1): membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	2
G protein-coupled receptor activity	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	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
signaling receptor activity	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

428 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADGRF4	ADGRA1	Q86SQ6	566
ADGRF4	ADGRA3	Q8IWK6	476
ADGRF4	ADGRA2	Q96PE1	456
ADGRF4	C5orf46	Q6UWT4	433
ADGRF4	WFDC5	Q8TCV5	423
ADGRF4	ZNF491	Q8N8L2	371
ADGRF4	OR4C46	A6NHA9	369
ADGRF4	ZNF530	Q6P9A1	369
ADGRF4	OR13J1	Q8NGT2	369
ADGRF4	GPR87	Q9BY21	348
ADGRF4	ANXA8L1	Q5VT79	338
ADGRF4	ADGRG4	Q8IZF6	335
ADGRF4	ADGRG5	Q8IZF4	332
ADGRF4	PRSS55	Q6UWB4	330
ADGRF4	SYNGR4	O95473	323

IntAct

4 interactions, top by confidence:

A	B	Type	Score
MEOX2	ADGRF4	psi-mi:“MI:0915”(physical association)	0.560
ADGRF4	MEOX2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (4): GPR115 (Two-hybrid), GPR115 (Proximity Label-MS), LRP1 (Cross-Linking-MS (XL-MS)), GPR115 (Affinity Capture-MS)

ESM2 similar proteins: D4A3T6, E1BPQ3, E9PU17, E9PX95, E9Q4J9, O35659, O60353, O88871, O88917, O88923, O94910, O95490, O95838, O97817, O97827, O97831, P30082, P32082, P32301, P43220, P48960, P49190, P70555, Q02644, Q58Y75, Q59I63, Q5IXF8, Q5T601, Q5U9X3, Q60755, Q6TAC4, Q7SY09, Q80TR1, Q80TS3, Q8IZF3, Q8IZF7, Q8JZZ7, Q8R420, Q8SQA4, Q8VEC3

Diamond homologs: A6QLU6, D4A3T6, E9Q4J9, G5E8Q8, Q2Q421, Q2Q426, Q58Y75, Q5T601, Q6QNK2, Q8IZF2, Q8IZF3, Q8IZF5, Q8IZF7, Q8VEC3, Q9BY15, Q9D2L6, Q9UHX3, Q9WVT0, C6KFA3, O97827, Q7Z7M1, Q80T32, Q80TS3, Q8CJ12, Q8SQA4, Q9HCU4, Q9QYP2, Q9R0M0, Q9Z0M6, Q9Z173, G5ECX0, P48960, Q9ESC1, Q9HAR2, Q14246, Q86SQ3, Q91ZE5, A1Z7G7, B3MFV7, B3N8M1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	96
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1690 predictions. Top by Δscore:

Variant	Effect	Δscore
6:47707339:G:GG	donor_gain	1.0000
6:47712529:G:GT	donor_gain	1.0000
6:47718385:TTAG:T	acceptor_loss	1.0000
6:47718387:A:AC	acceptor_loss	1.0000
6:47718387:A:AG	acceptor_gain	1.0000
6:47718388:G:GA	acceptor_gain	1.0000
6:47718388:GA:G	acceptor_gain	1.0000
6:47718388:GAAT:G	acceptor_gain	1.0000
6:47718443:AATG:A	donor_loss	1.0000
6:47718444:ATGT:A	donor_loss	1.0000
6:47718445:TG:T	donor_loss	1.0000
6:47718446:G:GG	donor_gain	1.0000
6:47718446:GTGA:G	donor_loss	1.0000
6:47718447:TGA:T	donor_loss	1.0000
6:47718448:GAG:G	donor_loss	1.0000
6:47698795:G:GG	donor_gain	0.9900
6:47699444:G:T	donor_gain	0.9900
6:47707335:AAAAG:A	donor_loss	0.9900
6:47707336:AAAGT:A	donor_loss	0.9900
6:47707337:AAG:A	donor_loss	0.9900
6:47707338:AG:A	donor_loss	0.9900
6:47707339:GTAAG:G	donor_loss	0.9900
6:47707340:TAA:T	donor_loss	0.9900
6:47707341:AAG:A	donor_loss	0.9900
6:47712463:G:GG	donor_gain	0.9900
6:47712773:TTTTC:T	donor_gain	0.9900
6:47713792:TTGCA:T	acceptor_loss	0.9900
6:47713794:GCA:G	acceptor_loss	0.9900
6:47713796:A:AG	acceptor_gain	0.9900
6:47713797:G:GC	acceptor_loss	0.9900

AlphaMissense

4625 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:47714322:G:C	W359C	0.997
6:47714322:G:T	W359C	0.997
6:47714488:A:C	S415R	0.994
6:47714490:C:A	S415R	0.994
6:47714490:C:G	S415R	0.994
6:47714320:T:A	W359R	0.992
6:47714320:T:C	W359R	0.992
6:47714301:G:C	W352C	0.988
6:47714301:G:T	W352C	0.988
6:47716806:G:C	G645R	0.988
6:47713851:G:C	W202C	0.986
6:47713851:G:T	W202C	0.986
6:47714580:T:A	N445K	0.985
6:47714580:T:G	N445K	0.985
6:47715154:T:C	F637L	0.984
6:47715156:T:A	F637L	0.984
6:47715156:T:G	F637L	0.984
6:47714299:T:A	W352R	0.983
6:47714299:T:C	W352R	0.983
6:47713849:T:A	W202R	0.978
6:47713849:T:C	W202R	0.978
6:47714404:T:C	F387L	0.978
6:47714406:T:A	F387L	0.978
6:47714406:T:G	F387L	0.978
6:47715097:T:A	W618R	0.978
6:47715097:T:C	W618R	0.978
6:47714290:T:A	C349S	0.976
6:47714291:G:C	C349S	0.976
6:47710854:T:A	C90S	0.974
6:47710855:G:C	C90S	0.974

dbSNP variants (sampled 300 via entrez): RS1000004754 (6:47717110 A>C), RS1000023765 (6:47701980 A>G,T), RS1000256603 (6:47696717 C>T), RS1000281286 (6:47696667 C>T), RS1000288839 (6:47707590 C>T), RS1000359961 (6:47712388 C>A), RS1000640845 (6:47707395 G>A), RS1000914071 (6:47707892 G>A), RS1000968520 (6:47713106 G>C), RS1001026078 (6:47703575 C>G,T), RS1001090606 (6:47697480 C>T), RS1001271740 (6:47720607 C>T), RS1001418565 (6:47713995 T>C), RS1001635206 (6:47710874 A>G), RS1001650287 (6:47719365 G>A)

Disease associations

OMIM: gene MIM:614268 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523889 (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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
(+)-JQ1 compound	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Aflatoxin B1	increases expression	2
aristolochic acid I	increases expression	1
methyleugenol	increases expression	1
propionaldehyde	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
CGP 52608	affects binding, increases reaction	1
NSC 689534	affects binding, increases expression	1
Air Pollutants	increases abundance, increases expression	1
Calcitriol	increases expression	1
Carbamazepine	affects expression	1
Copper	affects binding, increases expression	1
Demecolcine	increases expression	1
Endosulfan	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Formaldehyde	increases expression	1
Methyl Methanesulfonate	increases expression	1
N-Nitrosopyrrolidine	increases expression	1
Nickel	decreases expression	1
Silicon Dioxide	increases expression	1
Vincristine	increases expression	1
Cyclosporine	increases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	increases abundance, increases 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
CHEMBL4883399	Binding	PRESTO-Tango GPCRome screening (GPR115)	Data for DCP probe UCSF924

Clinical trials (associated diseases)

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