GPR33

Summary

GPR33 (G protein-coupled receptor 33, HGNC:4489) is a protein-coding gene on chromosome 14q12, encoding Probable G-protein coupled receptor 33 (Q49SQ1). Orphan receptor; could be a chemoattractant receptor.

This gene has been identified as an orphan chemoattractant G-protein-coupled receptors (GPCR) pseudogene. Studies have shown that the inactivated gene is present as the predominant allele in the human population. A small fraction of the human population has been found to harbor an intact allele.

Source: NCBI Gene 2856 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 59 total
• MANE Select transcript: NM_001197184

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4489
Approved symbol	GPR33
Name	G protein-coupled receptor 33
Location	14q12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000214943
Ensembl biotype	protein_coding
OMIM	610118
Entrez	2856

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000399285

RefSeq mRNA: 1 — MANE Select: NM_001197184 NM_001197184

CCDS: CCDS73628

Canonical transcript exons

ENST00000399285 — 2 exons

Exon	Start	End
ENSE00001537351	31482875	31483971
ENSE00003716091	31487897	31488039

Expression profiles

Bgee: expression breadth tissue_specific, 10 present calls, max score 43.10.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0389 / max 10.2286, expressed in 12 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142746	0.0389	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
duodenum	UBERON:0002114	43.10	silver quality
leukocyte	CL:0000738	42.49	silver quality
colonic epithelium	UBERON:0000397	42.10	gold quality
vermiform appendix	UBERON:0001154	41.92	gold quality
monocyte	CL:0000576	41.55	silver quality
lymph node	UBERON:0000029	40.54	gold quality
tonsil	UBERON:0002372	38.57	silver quality
granulocyte	CL:0000094	36.68	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
mucosa of transverse colon	UBERON:0004991	35.84	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
urinary bladder	UBERON:0001255	32.10	gold quality
rectum	UBERON:0001052	32.04	silver quality
bone marrow	UBERON:0002371	31.74	gold quality
endometrium	UBERON:0001295	31.68	gold quality
gall bladder	UBERON:0002110	31.56	gold quality
sural nerve	UBERON:0015488	30.93	gold quality
liver	UBERON:0002107	30.51	gold quality
prefrontal cortex	UBERON:0000451	30.07	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	27.58	gold quality
islet of Langerhans	UBERON:0000006	26.93	gold quality
kidney	UBERON:0002113	26.15	gold quality
placenta	UBERON:0001987	25.81	gold quality
muscle of leg	UBERON:0001383	25.27	gold quality
calcaneal tendon	UBERON:0003701	25.20	gold quality
right lobe of liver	UBERON:0001114	25.13	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.96

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 2)

• Cloning and analysis of more than 120 mammalian GPR33 orthologs from 16 of 18 eutherian orders revealed an inactivation of this chemoattractant GPCR not only in humans, but also in several great ape and rodent species. (PMID:15987686)
• These data indicate an important role of GPR33 function in innate immunity which became dispensable during human evolution most likely due to past or balancing selection. (PMID:20399748)

Cross-species orthologs

1 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gpr33	ENSMUSG00000035148

Paralogs (8): C5AR2 (ENSG00000134830), GPR32 (ENSG00000142511), FPR2 (ENSG00000171049), FPR1 (ENSG00000171051), C3AR1 (ENSG00000171860), CMKLR1 (ENSG00000174600), FPR3 (ENSG00000187474), C5AR1 (ENSG00000197405)

Protein

Protein identifiers

Probable G-protein coupled receptor 33 — Q49SQ1 (reviewed: Q49SQ1)

All UniProt accessions (1): Q49SQ1

UniProt curated annotations — full annotation on UniProt →

Function. Orphan receptor; could be a chemoattractant receptor.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in spleen, lung, heart, liver, kidney, pancreas, thymus, gonads and leukocytes.

Polymorphism. The sequence shown in this entry differs from the translation of the reference genome assembly (GRCh38/hg38) due to a nonsense variant creating stop codon at position 140 in the reference genome. The sequence shown in this entry is that of variant p.Ter140Arg. This variant has a frequency of about 1% in the human population according to the Genome Aggregation Database (gnomAD v3.1.2). Polymorphic GPR33 gene inactivation has been observed in hominoids, including chimpanzees, as well as in some rodents, such as rat, but not in other mammals. A likely cause of GPR33 inactivation by selection is its interplay with an exogenous factor, such as a rodent-hominoidotopic pathogen.

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

RefSeq proteins (1): NP_001184113* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR000826	Formyl_rcpt-rel	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (22 total): topological domain 8, transmembrane region 7, glycosylation site 4, chain 1, disulfide bond 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q49SQ1-F1	87.59	0.63

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): 101–179

Glycosylation sites (4): 5, 12, 19, 272

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 29 (showing top): GOBP_INFLAMMATORY_RESPONSE, chr14q12, GOBP_REGULATION_OF_IMMUNE_RESPONSE, FOSTER_TOLERANT_MACROPHAGE_DN, GOBP_PHOSPHOLIPASE_C_ACTIVATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, RASHI_RESPONSE_TO_IONIZING_RADIATION_5, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GOMF_G_PROTEIN_COUPLED_RECEPTOR_ACTIVITY, GOBP_ACTIVATION_OF_IMMUNE_RESPONSE, GOBP_COMPLEMENT_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_IMMUNE_RESPONSE_REGULATING_SIGNALING_PATHWAY, GOBP_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_QTL_TRANS, GOMF_COMPLEMENT_RECEPTOR_ACTIVITY, GOMF_IMMUNE_RECEPTOR_ACTIVITY

GO Biological Process (8): complement receptor mediated signaling pathway (GO:0002430), inflammatory response (GO:0006954), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), positive regulation of cytosolic calcium ion concentration (GO:0007204), cell communication (GO:0007154), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), signaling (GO:0023052)

GO Molecular Function (2): complement receptor activity (GO:0004875), 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 signaling pathway	2
cellular process	2
transmembrane signaling receptor activity	2
immune response-activating cell surface receptor signaling pathway	1
defense response	1
phospholipase C activator activity	1
regulation of biological quality	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
signal transduction	1
regulation of biological process	1
complement binding	1
complement receptor mediated signaling pathway	1
immune receptor activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

394 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPR33	DTD2	Q96FN9	570
GPR33	HEATR5A	Q86XA9	478
GPR33	UNC93A	Q86WB7	410
GPR33	CATSPER2	Q96P56	387
GPR33	NUBPL	Q8TB37	372
GPR33	GPR148	Q8TDV2	367
GPR33	GUCY2D	Q02846	365
GPR33	GSTA4	O15217	353
GPR33	COX6B1	P14854	353
GPR33	COX6B2	Q6YFQ2	353
GPR33	ADRA1B	P35368	345
GPR33	KCNE2	Q9Y6J6	325
GPR33	GPR157	Q5UAW9	320
GPR33	NBPF14	Q5TI25	310
GPR33	GPR150	Q8NGU9	307

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A4FUQ5, B9VR26, O08790, O35786, O70129, O75388, O88416, O88536, O88537, O97664, P0C7U4, P21462, P21730, P25089, P25090, P30992, P30993, P33766, P35343, P35407, P46090, P46091, P79175, P79176, P79177, P79178, P79188, P79189, P79190, P79191, P79234, P79235, P79236, P79237, P79240, P79241, P79242, P79243, P97468, P97520

Diamond homologs: A4FUQ5, B1PHQ8, B9VR26, O08565, O08790, O35210, O35786, O62747, O70129, O75388, O77590, O88416, O88536, O88537, O97571, O97664, P0C7U4, P0C7U5, P21462, P21730, P25025, P25089, P25090, P25095, P25104, P28646, P29089, P29754, P29755, P30555, P30556, P30872, P30873, P30937, P30992, P30993, P31391, P33766, P34976, P35373

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	54
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

92 predictions. Top by Δscore:

Variant	Effect	Δscore
14:31483969:GACC:G	acceptor_loss	0.9900
14:31483970:ACCT:A	acceptor_loss	0.9900
14:31483971:CCTG:C	acceptor_loss	0.9900
14:31483972:C:CG	acceptor_loss	0.9900
14:31483973:T:G	acceptor_loss	0.9900
14:31483729:CAT:C	acceptor_gain	0.9800
14:31483731:T:TC	acceptor_gain	0.9800
14:31483972:C:CC	acceptor_gain	0.9700
14:31483968:TGAC:T	acceptor_gain	0.9600
14:31487895:ACCTC:A	donor_loss	0.9500
14:31487896:C:CA	donor_loss	0.9500
14:31487898:TCAG:T	donor_gain	0.9500
14:31483987:CAG:C	acceptor_gain	0.9400
14:31483731:T:C	acceptor_gain	0.9200
14:31483734:T:TC	acceptor_gain	0.9200
14:31483979:G:C	acceptor_gain	0.9200
14:31483988:A:T	acceptor_gain	0.9100
14:31487895:A:AC	donor_gain	0.9100
14:31487896:C:CC	donor_gain	0.9100
14:31483916:A:AC	donor_gain	0.9000
14:31483917:C:CC	donor_gain	0.9000
14:31483979:G:GC	acceptor_gain	0.9000
14:31487896:CCT:C	donor_gain	0.8800
14:31487895:ACCT:A	donor_gain	0.8700
14:31487896:CCTC:C	donor_gain	0.8700
14:31487897:CTCA:C	donor_gain	0.8700
14:31483974:G:GC	acceptor_gain	0.8600
14:31483969:GAC:G	acceptor_gain	0.8500
14:31483989:G:GC	acceptor_gain	0.8500
14:31483734:T:C	acceptor_gain	0.8400

AlphaMissense

2195 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:31483684:C:A	W94C	0.979
14:31483684:C:G	W94C	0.979
14:31483204:G:C	F254L	0.977
14:31483204:G:T	F254L	0.977
14:31483206:A:G	F254L	0.977
14:31483486:G:C	S160R	0.976
14:31483486:G:T	S160R	0.976
14:31483488:T:G	S160R	0.976
14:31483324:A:C	F214L	0.975
14:31483324:A:T	F214L	0.975
14:31483326:A:G	F214L	0.975
14:31483509:A:G	W153R	0.968
14:31483509:A:T	W153R	0.968
14:31483839:C:G	G43R	0.968
14:31483664:C:G	C101S	0.967
14:31483665:A:T	C101S	0.967
14:31483838:C:T	G43D	0.967
14:31483589:C:G	R126P	0.965
14:31483430:C:G	C179S	0.963
14:31483431:A:T	C179S	0.963
14:31483197:A:G	C257R	0.960
14:31483686:A:G	W94R	0.959
14:31483686:A:T	W94R	0.959
14:31483825:A:C	N47K	0.958
14:31483825:A:T	N47K	0.958
14:31483599:C:G	G123R	0.956
14:31483627:G:C	F113L	0.956
14:31483627:G:T	F113L	0.956
14:31483629:A:G	F113L	0.956
14:31483757:A:G	L70P	0.955

dbSNP variants (sampled 300 via entrez): RS1000037707 (14:31486817 T>C), RS1000410262 (14:31486541 G>A), RS1001187417 (14:31486025 G>A), RS1001456781 (14:31485361 C>T), RS1001849816 (14:31489332 A>C), RS1001901894 (14:31489065 T>C), RS1001994831 (14:31484206 G>A), RS1002193355 (14:31484701 T>C), RS1002330751 (14:31484487 T>A,C), RS1003189939 (14:31483292 T>A), RS1003327329 (14:31482981 C>A,T), RS1003483950 (14:31488965 T>C), RS1003983023 (14:31484427 C>T), RS1004120202 (14:31483957 C>A,G,T), RS1004989921 (14:31482920 C>A,T)

Disease associations

OMIM: gene MIM:610118 | disease phenotypes: MIM:616487

GenCC curated gene-disease

Mondo (1): epidermolysis bullosa simplex with nail dystrophy (MONDO:0014661)

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: no

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 no pharmacology

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

Ligand	Action	Affinity	Parameter
cortisol	Binding	7.92	pKd

Clinical trials (associated diseases)

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