GPR21

Summary

GPR21 (G protein-coupled receptor 21, HGNC:4476) is a protein-coding gene on chromosome 9q33.2, encoding Probable G-protein coupled receptor 21 (Q99679). Orphan receptor.

This gene 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. The encoded protein activates a Gq signal transduction pathway which mobilizes calcium.

Source: NCBI Gene 2844 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 48 total
• Druggable target: yes
• MANE Select transcript: NM_005294

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4476
Approved symbol	GPR21
Name	G protein-coupled receptor 21
Location	9q33.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000188394
Ensembl biotype	protein_coding
OMIM	601909
Entrez	2844

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000616002

RefSeq mRNA: 1 — MANE Select: NM_005294 NM_005294

CCDS: CCDS6849

Canonical transcript exons

ENST00000616002 — 2 exons

Exon	Start	End
ENSE00003728523	123033667	123033742
ENSE00003732022	123034171	123035665

Expression profiles

Bgee: expression breadth ubiquitous, 138 present calls, max score 85.29.

FANTOM5 (CAGE): breadth broad, TPM avg 2.1208 / max 215.3042, expressed in 285 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
98435	2.1208	285

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
diaphragm	UBERON:0001103	85.29	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.25	gold quality
cortical plate	UBERON:0005343	82.98	gold quality
type B pancreatic cell	CL:0000169	81.29	gold quality
olfactory bulb	UBERON:0002264	81.26	gold quality
right coronary artery	UBERON:0001625	78.95	gold quality
popliteal artery	UBERON:0002250	75.59	gold quality
tibial artery	UBERON:0007610	75.56	gold quality
left coronary artery	UBERON:0001626	75.35	gold quality
coronary artery	UBERON:0001621	74.82	gold quality
cervix squamous epithelium	UBERON:0006922	73.50	gold quality
vastus lateralis	UBERON:0001379	73.20	gold quality
quadriceps femoris	UBERON:0001377	72.85	gold quality
aorta	UBERON:0000947	71.87	gold quality
triceps brachii	UBERON:0001509	71.10	gold quality
ganglionic eminence	UBERON:0004023	71.04	gold quality
descending thoracic aorta	UBERON:0002345	70.95	gold quality
gluteal muscle	UBERON:0002000	70.44	gold quality
embryo	UBERON:0000922	69.69	gold quality
secondary oocyte	CL:0000655	69.53	gold quality
prefrontal cortex	UBERON:0000451	69.52	gold quality
orbitofrontal cortex	UBERON:0004167	69.18	gold quality
epithelial cell of pancreas	CL:0000083	68.71	gold quality
pancreatic ductal cell	CL:0002079	68.38	silver quality
thymus	UBERON:0002370	67.81	gold quality
thoracic aorta	UBERON:0001515	67.08	gold quality
ascending aorta	UBERON:0001496	66.53	gold quality
cervix epithelium	UBERON:0004801	66.41	gold quality
skeletal muscle tissue	UBERON:0001134	65.93	gold quality
endothelial cell	CL:0000115	65.83	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.67

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 4)

• GPR21 is up-regulated in type 2 diabetes. (PMID:27243589)
• Deletion of GPR21 improves glucose homeostasis and inhibits the CCL2-CCR2 axis by divergent mechanisms. (PMID:34782333)
• G protein-coupled receptor 21 in macrophages: An in vitro study. (PMID:35537492)
• Cryo-EM structures of orphan GPR21 signaling complexes. (PMID:36639690)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gpr21	ENSMUSG00000053164
rattus_norvegicus	Gpr21	ENSRNOG00000078766

Paralogs (25): DRD4 (ENSG00000069696), HRH3 (ENSG00000101180), HRH2 (ENSG00000113749), CHRM3 (ENSG00000133019), HRH4 (ENSG00000134489), TAAR5 (ENSG00000135569), GPR84 (ENSG00000139572), GPR161 (ENSG00000143147), TAAR2 (ENSG00000146378), TAAR6 (ENSG00000146383), TAAR8 (ENSG00000146385), TAAR1 (ENSG00000146399), DRD3 (ENSG00000151577), HTR4 (ENSG00000164270), CHRM1 (ENSG00000168539), DRD5 (ENSG00000169676), HTR1A (ENSG00000178394), HTR1D (ENSG00000179546), CHRM4 (ENSG00000180720), CHRM2 (ENSG00000181072), DRD1 (ENSG00000184845), CHRM5 (ENSG00000184984), HRH1 (ENSG00000196639), GPR52 (ENSG00000203737), TAAR9 (ENSG00000237110)

Protein

Protein identifiers

Probable G-protein coupled receptor 21 — Q99679 (reviewed: Q99679)

All UniProt accessions (2): Q99679, H9NIL4

UniProt curated annotations — full annotation on UniProt →

Function. Orphan receptor.

Subcellular location. Cell membrane.

Tissue specificity. Not detected in the brain regions thalamus, putamen, caudate, frontal cortex, pons, hypothalamus, hippocampus.

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

RefSeq proteins (1): NP_005285* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR050569	TAAR	Family

Pfam: PF00001

UniProt features (34 total): helix 12, topological domain 8, transmembrane region 7, glycosylation site 2, strand 2, turn 2, chain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8HMV	ELECTRON MICROSCOPY	2.91
8HIX	ELECTRON MICROSCOPY	3.12
8HJ0	ELECTRON MICROSCOPY	3.12
8HJ1	ELECTRON MICROSCOPY	3.27
8HJ2	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99679-F1	83.75	0.54

Antibody-complex structures (SAbDab): 5 — 8HIX, 8HJ0, 8HJ1, 8HJ2, 8HMV

Functional residue map

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

Glycosylation sites (2): 2, 8

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 80 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, RRAGTTGT_UNKNOWN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, CMYB_01, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, GOBP_GROWTH, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, CAGCTG_AP4_Q5, GOBP_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_REGULATION_OF_MULTICELLULAR_ORGANISM_GROWTH, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_RESPONSE_TO_INSULIN

GO Biological Process (6): G protein-coupled receptor signaling pathway (GO:0007186), insulin receptor signaling pathway (GO:0008286), positive regulation of multicellular organism growth (GO:0040018), glucose homeostasis (GO:0042593), negative regulation of insulin receptor signaling pathway (GO:0046627), signal transduction (GO:0007165)

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

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor activity	1
signal transduction	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
multicellular organism growth	1
regulation of multicellular organism growth	1
positive regulation of developmental growth	1
positive regulation of multicellular organismal process	1
carbohydrate homeostasis	1
insulin receptor signaling pathway	1
negative regulation of signal transduction	1
regulation of insulin receptor signaling pathway	1
negative regulation of cellular response to insulin stimulus	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

317 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPR21	GPR20	Q99678	938
GPR21	RC3H2	Q9HBD1	527
GPR21	STRBP	Q96SI9	431
GPR21	RABGAP1	Q9Y3P9	403
GPR21	GPR12	P47775	390
GPR21	TMEM71	Q6P5X7	374
GPR21	CRB2	Q5IJ48	358
GPR21	RGR	P47804	341
GPR21	GOLGA1	Q92805	331
GPR21	SGK2	Q9HBY8	320
GPR21	GNA14	O95837	291
GPR21	AASS	Q9UDR5	290
GPR21	GNA15	P30679	269
GPR21	IMPG1	Q17R60	257
GPR21	TANC1	Q9C0D5	256
GPR21	ALG3	Q92685	256

IntAct

13 interactions, top by confidence:

A	B	Type	Score
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
RAMP1	GPR21	psi-mi:“MI:0915”(physical association)	0.400
GPR21	RAMP1	psi-mi:“MI:0915”(physical association)	0.400
GPR21	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	GPR21	psi-mi:“MI:0915”(physical association)	0.400
RAMP3	GPR21	psi-mi:“MI:0915”(physical association)	0.400
GPR21	RAMP3	psi-mi:“MI:0915”(physical association)	0.400
GPR21	ATP13A2	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (144): MARCH6 (Affinity Capture-MS), ERMP1 (Affinity Capture-MS), OTUD6A (Affinity Capture-MS), S1PR5 (Affinity Capture-MS), FZD3 (Affinity Capture-MS), SIDT2 (Affinity Capture-MS), ZDHHC5 (Affinity Capture-MS), SLC6A6 (Affinity Capture-MS), SLC15A4 (Affinity Capture-MS), SLC47A1 (Affinity Capture-MS), ADCY9 (Affinity Capture-MS), FZD2 (Affinity Capture-MS), EDA (Affinity Capture-MS), CNNM1 (Affinity Capture-MS), VEZT (Affinity Capture-MS)

ESM2 similar proteins: A0A678XMK4, A6QLE7, G3M4F8, O08890, O42384, O42574, O70528, P07550, P0C5J4, P10608, P17124, P18762, P25021, P25102, P28221, P28222, P28334, P28564, P28565, P28566, P30939, P30940, P35404, P35406, P46636, P47747, P56496, P60020, P60021, P61752, P79748, P97288, Q02284, Q0EAB5, Q13639, Q28044, Q28509, Q588Y6, Q61224, Q62758

Diamond homologs: A0T2N3, A6QLE7, O02213, O15973, O19091, O46635, O60755, O77621, O77721, P08908, P08909, P0C5J4, P11613, P14842, P18599, P19327, P22270, P25102, P28223, P28286, P34968, P35363, P41595, P46093, P50128, P50129, P50132, P56481, P79960, Q0EAB6, Q1JQB3, Q25321, Q25322, Q2TAD5, Q4KLH9, Q4LBB6, Q4VA82, Q5IS66, Q5R4Q6, Q60F97

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	45
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

344 predictions. Top by Δscore:

Variant	Effect	Δscore
9:123035068:T:A	acceptor_gain	0.9100
9:123035066:ACTGG:A	acceptor_gain	0.8700
9:123035069:G:A	acceptor_gain	0.8700
9:123035066:ACTG:A	acceptor_gain	0.8600
9:123034992:ACCCT:A	acceptor_gain	0.8300
9:123035066:ACT:A	acceptor_gain	0.8300
9:123034170:GCT:G	acceptor_gain	0.8100
9:123034657:G:GT	donor_gain	0.8000
9:123034252:ACTT:A	acceptor_gain	0.7900
9:123034255:T:A	acceptor_gain	0.7600
9:123034247:C:G	acceptor_gain	0.7400
9:123034589:A:AG	donor_gain	0.7300
9:123034993:C:G	acceptor_gain	0.7300
9:123034246:A:AG	acceptor_gain	0.6400
9:123035359:T:TA	acceptor_gain	0.6400
9:123035203:A:AG	acceptor_gain	0.6200
9:123034992:A:AG	acceptor_gain	0.6100
9:123035066:A:AG	acceptor_gain	0.6100
9:123035207:T:G	acceptor_gain	0.6100
9:123035042:T:TA	acceptor_gain	0.6000
9:123035206:A:AG	acceptor_gain	0.5800
9:123034166:A:T	acceptor_gain	0.5700
9:123034378:G:GT	donor_gain	0.5700
9:123034169:A:AG	acceptor_gain	0.5600
9:123034170:G:GG	acceptor_gain	0.5600
9:123034727:ACTGT:A	acceptor_gain	0.5600
9:123034728:C:G	acceptor_gain	0.5500
9:123034996:T:TA	acceptor_gain	0.5500
9:123035103:GTGGT:G	acceptor_gain	0.5500
9:123035387:T:A	acceptor_gain	0.5400

AlphaMissense

2315 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:123034936:A:C	S124R	0.999
9:123034938:C:A	S124R	0.999
9:123034938:C:G	S124R	0.999
9:123035026:T:A	W154R	0.999
9:123035026:T:C	W154R	0.999
9:123035347:T:C	F261L	0.999
9:123035349:T:A	F261L	0.999
9:123035349:T:G	F261L	0.999
9:123034704:C:A	N46K	0.998
9:123034704:C:G	N46K	0.998
9:123034789:G:C	D75H	0.998
9:123034790:A:C	D75A	0.998
9:123034790:A:G	D75G	0.998
9:123034790:A:T	D75V	0.998
9:123034791:C:A	D75E	0.998
9:123034791:C:G	D75E	0.998
9:123034801:G:A	G79R	0.998
9:123034801:G:C	G79R	0.998
9:123034801:G:T	G79W	0.998
9:123034802:G:A	G79E	0.998
9:123035359:T:A	W265R	0.998
9:123035359:T:C	W265R	0.998
9:123035366:C:A	P267Q	0.998
9:123035366:C:G	P267R	0.998
9:123035449:A:C	S295R	0.998
9:123035451:T:A	S295R	0.998
9:123035451:T:G	S295R	0.998
9:123035454:C:A	N296K	0.998
9:123035454:C:G	N296K	0.998
9:123035455:A:C	S297R	0.998

dbSNP variants (sampled 300 via entrez): RS1000024059 (9:123036317 G>A), RS1000054792 (9:123036678 A>G), RS1000190344 (9:123047171 T>C,G), RS1000282955 (9:123043895 A>C,G,T), RS1000327249 (9:123049569 T>C,G), RS1000665010 (9:123048135 C>G,T), RS1000888901 (9:123035977 TAA>T), RS1001489086 (9:123032798 A>G), RS1001521616 (9:123033185 G>C), RS1001641883 (9:123032868 G>A,C,T), RS1002046539 (9:123039668 G>A), RS1002211032 (9:123045315 A>G), RS1002491966 (9:123034472 A>G,T), RS1002846223 (9:123047786 G>A), RS1002877323 (9:123047964 G>T)

Disease associations

OMIM: gene MIM:601909 | 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
GCST005951_64	Body mass index	2.000000e-10
GCST008362_190	Birth weight	6.000000e-16
GCST009616_3	HDL cholesterol levels x thiazide or thiazide-like diuretics use interaction	7.000000e-07
GCST010703_296	Brain morphology (MOSTest)	2.000000e-14

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004344	birth weight
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523913 (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 only surrogate ligands

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
cinnamaldehyde	increases expression	1
cobaltous chloride	increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
epigallocatechin gallate	increases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
Sunitinib	increases expression	1
Cadmium	decreases expression	1
T-2 Toxin	decreases expression	1
Valproic Acid	decreases methylation	1
Vanadates	decreases expression	1
Lactic Acid	affects 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
CHEMBL4883439	Binding	PRESTO-Tango GPCRome screening (GPR21)	Data for DCP probe UCSF924

Clinical trials (associated diseases)

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