GPR25

Summary

GPR25 (G protein-coupled receptor 25, HGNC:4480) is a protein-coding gene on chromosome 1q32.1, encoding C-X-C chemokine receptor GPR25 (O00155). Receptor for the C-X-C chemokine CXCL17, which plays a key role in lymphocyte homing.

This gene is intronless and encodes a member of the G-protein coupled receptor 1 family. G-protein coupled receptors are membrane proteins which activate signaling cascades as a response to extracellular stress. This gene has been linked to arterial stiffness.

Source: NCBI Gene 2848 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 45 total
• Druggable target: yes
• MANE Select transcript: NM_005298

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4480
Approved symbol	GPR25
Name	G protein-coupled receptor 25
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000170128
Ensembl biotype	protein_coding
OMIM	602174
Entrez	2848

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000304244

RefSeq mRNA: 1 — MANE Select: NM_005298 NM_005298

CCDS: CCDS1405

Canonical transcript exons

ENST00000304244 — 1 exons

Exon	Start	End
ENSE00001159564	200872981	200874178

Expression profiles

Bgee: expression breadth broad, 57 present calls, max score 85.33.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2040 / max 35.6376, expressed in 58 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
7663	0.2040	58

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.33	gold quality
granulocyte	CL:0000094	73.36	gold quality
bone marrow cell	CL:0002092	58.24	gold quality
blood	UBERON:0000178	56.86	gold quality
vermiform appendix	UBERON:0001154	51.53	gold quality
caecum	UBERON:0001153	50.09	gold quality
right uterine tube	UBERON:0001302	49.62	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
skin of hip	UBERON:0001554	49.27	silver quality
body of stomach	UBERON:0001161	49.19	gold quality
spleen	UBERON:0002106	49.03	gold quality
middle temporal gyrus	UBERON:0002771	48.95	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
fundus of stomach	UBERON:0001160	47.30	gold quality
periodontal ligament	UBERON:0008266	47.14	gold quality
stomach	UBERON:0000945	46.93	gold quality
renal glomerulus	UBERON:0000074	46.86	gold quality
metanephric glomerulus	UBERON:0004736	46.77	gold quality
nephron tubule	UBERON:0001231	46.71	gold quality
lower esophagus mucosa	UBERON:0035834	45.40	silver quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	45.35	gold quality
inferior olivary complex	UBERON:0002127	45.14	gold quality
nasal cavity epithelium	UBERON:0005384	44.87	gold quality
cranial nerve II	UBERON:0000941	43.62	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
bone marrow	UBERON:0002371	43.33	gold quality
amniotic fluid	UBERON:0000173	43.00	gold quality
esophagus mucosa	UBERON:0002469	42.96	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
pharyngeal mucosa	UBERON:0000355	42.51	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.86

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 1)

• GPR-25 is homologous to receptors involved in blood pressure regulation. (PMID:17386346)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gpr25	ENSDARG00000057112
mus_musculus	Gpr25	ENSMUSG00000052759
rattus_norvegicus	Gpr25	ENSRNOG00000008603

Paralogs (7): BDKRB1 (ENSG00000100739), APLNR (ENSG00000134817), AGTR1 (ENSG00000144891), GPR15 (ENSG00000154165), BDKRB2 (ENSG00000168398), RXFP4 (ENSG00000173080), AGTR2 (ENSG00000180772)

Protein

Protein identifiers

C-X-C chemokine receptor GPR25 — O00155 (reviewed: O00155)

Alternative names: G-protein coupled receptor 25

All UniProt accessions (1): O00155

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for the C-X-C chemokine CXCL17, which plays a key role in lymphocyte homing. 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. Activation by CXCL17 on lymphocytes activates the RhoA pathway, which regulates cytoskeletal dynamics and integrins, mediating lymphocyte recruitment into the respiratory, upper gastrointestinal, biliary and genito-urinary tracts.

Subcellular location. Cell membrane.

Tissue specificity. Present on activated B- and T-cells.

Induction. Induced on innate lymphocytes before emigration to the periphery.

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

RefSeq proteins (1): NP_005289* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR050119	CCR1-9-like	Family

Pfam: PF00001

UniProt features (19 total): topological domain 8, transmembrane region 7, mutagenesis site 2, chain 1, disulfide bond 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00155-F1	82.48	0.59

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 (1): 112–191

Mutagenesis-validated functional residues (2):

Position	Phenotype
95	abolished ability to be activated by cxcl17.
178	abolished ability to be activated by cxcl17.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 73 (showing top): GOBP_CELL_CHEMOTAXIS, GOBP_RESPONSE_TO_PEPTIDE, GOBP_LEUKOCYTE_CHEMOTAXIS, GOBP_TAXIS, GOBP_LEUKOCYTE_MIGRATION, GOBP_LYMPHOCYTE_CHEMOTAXIS, GOBP_LYMPHOCYTE_MIGRATION, NERF_Q2, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GOMF_G_PROTEIN_COUPLED_CHEMOATTRACTANT_RECEPTOR_ACTIVITY, GOMF_G_PROTEIN_COUPLED_RECEPTOR_ACTIVITY, MARTENS_TRETINOIN_RESPONSE_UP, GOBP_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_MONONUCLEAR_CELL_MIGRATION, GOBP_RESPONSE_TO_CHEMOKINE

GO Biological Process (6): G protein-coupled receptor signaling pathway (GO:0007186), leukocyte chemotaxis (GO:0030595), lymphocyte chemotaxis (GO:0048247), chemokine-mediated signaling pathway (GO:0070098), lymphocyte migration into lymphoid organs (GO:0097021), signal transduction (GO:0007165)

GO Molecular Function (3): G protein-coupled receptor activity (GO:0004930), C-X-C chemokine receptor activity (GO:0016494), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lymphocyte migration	2
G protein-coupled receptor signaling pathway	2
G protein-coupled receptor activity	1
signal transduction	1
leukocyte migration	1
cell chemotaxis	1
leukocyte chemotaxis	1
cytokine-mediated signaling pathway	1
cellular response to chemokine	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transmembrane signaling receptor activity	1
chemokine receptor activity	1
C-X-C chemokine binding	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

320 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPR25	GPR27	Q9NS67	512
GPR25	OR7C2	O60412	511
GPR25	GPR62	Q9BZJ7	509
GPR25	TCTA	P57738	508
GPR25	OR5C1	Q8NGR4	460
GPR25	KIF21B	O75037	453
GPR25	GPR162	Q16538	436
GPR25	INAVA	Q3KP66	435
GPR25	GPR52	Q9Y2T5	422
GPR25	POLR3A	O14802	420
GPR25	BLOC1S3	Q6QNY0	420
GPR25	PRSS54	Q6PEW0	414
GPR25	GPR176	Q14439	409
GPR25	GPR150	Q8NGU9	407
GPR25	PNPT1	Q8TCS8	400

IntAct

112 interactions, top by confidence:

A	B	Type	Score
CREB3L1	GPR25	psi-mi:“MI:0915”(physical association)	0.780
GPR25	CREB3L1	psi-mi:“MI:0915”(physical association)	0.780
GPR25	KASH5	psi-mi:“MI:0915”(physical association)	0.720
GGT7	GPR25	psi-mi:“MI:0915”(physical association)	0.720
KASH5	GPR25	psi-mi:“MI:0915”(physical association)	0.720
GPR25	GGT7	psi-mi:“MI:0915”(physical association)	0.720
GPR25	FATE1	psi-mi:“MI:0915”(physical association)	0.700
FATE1	GPR25	psi-mi:“MI:0915”(physical association)	0.700
GPR25	VAPB	psi-mi:“MI:0915”(physical association)	0.560
NAALADL2	GPR25	psi-mi:“MI:0915”(physical association)	0.560
PNMA1	GPR25	psi-mi:“MI:0915”(physical association)	0.560
VAPB	GPR25	psi-mi:“MI:0915”(physical association)	0.560
GPR25	NAALADL2	psi-mi:“MI:0915”(physical association)	0.560
GPR25	PNMA1	psi-mi:“MI:0915”(physical association)	0.560
GPR25	ATP6V0E1	psi-mi:“MI:0915”(physical association)	0.560
GPR25	SHISAL1	psi-mi:“MI:0915”(physical association)	0.560
GPR25	SLC35E3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (36): GPR25 (Two-hybrid), VAPB (Two-hybrid), PNMA1 (Two-hybrid), FATE1 (Two-hybrid), CREB3L1 (Two-hybrid), CCDC155 (Two-hybrid), NAALADL2 (Two-hybrid), GPR25 (Two-hybrid), GPR25 (Two-hybrid), GPR25 (Two-hybrid), GPR25 (Two-hybrid), GPR25 (Two-hybrid), GPR25 (Two-hybrid), GPR25 (Two-hybrid), GPR25 (Two-hybrid)

ESM2 similar proteins: A0A6I8PUB9, O00155, O00270, O14842, O14843, O15529, O43603, O46685, O60755, O88626, O88634, O88853, O88854, O88855, P0C5I1, P46092, P46093, P50132, Q149R9, Q15722, Q15743, Q1JQB3, Q3T181, Q3UFD7, Q3ZC80, Q4KLH9, Q6XKD3, Q76JU8, Q76JU9, Q76JV1, Q86VZ1, Q8BUD0, Q8BYC4, Q8HYC3, Q8K3T4, Q8TDS5, Q8TDU9, Q920E0, Q924U0, Q96G91

Diamond homologs: A0A287A2K5, C8YUV0, O00155, O02836, O08786, O15973, O18935, O19012, O19014, O19025, O19032, O19054, O19091, O62729, O77408, O77700, O77721, O77830, O97665, O97772, P04761, P08482, P0C5I1, P11229, P12657, P17200, P18089, P19328, P22270, P25021, P30545, P30551, P30552, P30553, P30796, P32211, P32238, P32239, P32302, P46627

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GPR25	“up-regulates activity”	GNAI1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 33 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
Transport of small molecules	5	6.6×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	43
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

66 predictions. Top by Δscore:

Variant	Effect	Δscore
1:200873846:C:T	donor_gain	0.5500
1:200873789:GCAC:G	donor_gain	0.5400
1:200873790:C:T	donor_gain	0.5100
1:200873150:GC:G	donor_gain	0.4900
1:200873477:C:T	donor_gain	0.4800
1:200873792:C:G	donor_gain	0.4800
1:200873739:C:G	donor_gain	0.4600
1:200873681:T:TA	acceptor_gain	0.4500
1:200873743:G:A	donor_gain	0.4500
1:200873795:T:A	donor_gain	0.4400
1:200873684:T:TA	donor_gain	0.4300
1:200873757:G:GT	donor_gain	0.4200
1:200873966:T:A	acceptor_gain	0.4000
1:200873793:G:GG	donor_gain	0.3900
1:200873764:C:G	donor_gain	0.3800
1:200873151:C:G	donor_gain	0.3700
1:200873786:A:T	donor_gain	0.3700
1:200873937:C:G	donor_gain	0.3600
1:200873462:TG:T	donor_gain	0.3500
1:200873711:T:G	acceptor_gain	0.3500
1:200873740:G:GG	donor_gain	0.3500
1:200873707:C:A	acceptor_gain	0.3400
1:200873754:G:GT	donor_gain	0.3400
1:200873698:T:TA	acceptor_gain	0.3300
1:200873796:T:A	donor_gain	0.3300
1:200873935:A:AG	acceptor_gain	0.3300
1:200873936:G:GG	acceptor_gain	0.3300
1:200873936:GCTGC:G	acceptor_gain	0.3300
1:200873936:GCT:G	acceptor_gain	0.3200
1:200873704:T:A	acceptor_gain	0.3000

AlphaMissense

2229 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:200873352:G:C	W105C	0.996
1:200873352:G:T	W105C	0.996
1:200873437:A:C	S134R	0.992
1:200873439:C:A	S134R	0.992
1:200873439:C:G	S134R	0.992
1:200873794:T:C	F253L	0.992
1:200873796:T:A	F253L	0.992
1:200873796:T:G	F253L	0.992
1:200873380:A:C	S115R	0.991
1:200873382:C:A	S115R	0.991
1:200873382:C:G	S115R	0.991
1:200873371:T:A	C112S	0.989
1:200873372:G:C	C112S	0.989
1:200873935:A:C	S300R	0.989
1:200873937:C:A	S300R	0.989
1:200873937:C:G	S300R	0.989
1:200873315:C:A	P93Q	0.987
1:200873350:T:A	W105R	0.987
1:200873350:T:C	W105R	0.987
1:200873926:T:C	F297L	0.987
1:200873928:C:A	F297L	0.987
1:200873928:C:G	F297L	0.987
1:200873208:C:A	N57K	0.986
1:200873208:C:G	N57K	0.986
1:200873315:C:G	P93R	0.986
1:200873194:G:C	G53R	0.985
1:200873372:G:A	C112Y	0.985
1:200873813:C:G	P259R	0.984
1:200873291:A:T	D85V	0.983
1:200873527:T:A	W164R	0.983

dbSNP variants (sampled 300 via entrez): RS1000116139 (1:200871958 C>T), RS1000420389 (1:200872330 T>G), RS1001731879 (1:200871404 A>G), RS1003585136 (1:200874479 C>A), RS1004056585 (1:200871146 C>T), RS1004318049 (1:200872678 G>A,C,T), RS1005010378 (1:200871142 C>T), RS1005678983 (1:200872518 C>G,T), RS1005729916 (1:200872847 C>T), RS1008409196 (1:200874183 G>A,C), RS1008570637 (1:200874417 G>A), RS1009108030 (1:200872460 C>T), RS1011230496 (1:200873880 G>A,C), RS1012857043 (1:200873133 C>T), RS1013196068 (1:200873457 C>G,T)

Disease associations

OMIM: gene MIM:602174 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005529_17	Ankylosing spondylitis	7.000000e-16
GCST005529_35	Ankylosing spondylitis	2.000000e-15
GCST010002_373	Refractive error	1.000000e-52
GCST010571_8	Autoimmune thyroid disease	3.000000e-09

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523858 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Class A Orphans with emerging pharmacology

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	decreases expression, increases abundance, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
butyraldehyde	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
theaflavin-3,3’-digallate	affects expression	1
Benzo(a)pyrene	increases methylation	1
Carmustine	decreases expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
Valproic Acid	increases methylation	1
p-Chloromercuribenzoic Acid	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
CHEMBL4883441	Binding	PRESTO-Tango GPCRome screening (GPR25)	Data for DCP probe UCSF924

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_KX52	PathHunter CHO-K1 GPR25 beta-arrestin	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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