GPR52

Chr 1

G protein-coupled receptor 52

NCBI Gene: 9293 ENSG00000203737 UniProt: Q9Y2T5 OMIM: 604106

GPR52 encodes a Gs-coupled receptor that is activated by antipsychotics and modulates dopamine signaling pathways in the striatum, affecting locomotor activity and huntingtin protein levels through cAMP-dependent mechanisms. Mutations in GPR52 cause neurodevelopmental disorders with developmental delays and behavioral abnormalities, inherited in an autosomal recessive pattern. The gene shows low constraint against loss-of-function variants, consistent with recessive inheritance where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, UniProt

Members of the G protein-coupled receptor (GPR) family play important roles in signal transduction from the external environment to the inside of the cell.[supplied by OMIM, Jul 2002]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.93

Clinical Summary— GPR52

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

39 VUS of 41 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.93LOEUF

pLI 0.010

Z-score 1.74

OE 0.44 (0.23–0.93)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.78Z-score

OE missense 0.84 (0.74–0.96)

168 obs / 199.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.23–0.93)

0≤0.351.4

Missense OE?0.84 (0.74–0.96)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 5 / 11.3Missense obs/exp: 168 / 199.0Syn Z: 0.76

This gene — mechanism propensity

0.77top 25%

GOF

0.82top 10%

LOF

0.2288th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

41 submitted variants in ClinVar

ClinVar

Classification Summary

VUS39

Likely Benign1

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	39	39
Likely Benign	1	1
Benign	1	1
Total	41	41

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

33 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap GPR52 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →