GPR157

Chr 1

G protein-coupled receptor 157

NCBI Gene: 80045 ENSG00000180758 UniProt: Q5UAW9 OMIM: 620860

This orphan G protein-coupled receptor promotes neuronal differentiation of radial glial progenitors through G(q)-protein signaling that activates phosphatidylinositol-calcium second messenger pathways. Mutations cause autosomal recessive developmental delay with variable intellectual disability and autism spectrum disorder. The gene shows tolerance to loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable G protein-coupled receptor activity. Predicted to be involved in adenylate cyclase-activating G protein-coupled receptor signaling pathway; phospholipase C-activating G protein-coupled receptor signaling pathway; and radial glial cell differentiation. Predicted to be located in ciliary membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.19

Clinical Summary— GPR157

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

58 VUS of 66 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.19LOEUF

pLI 0.001

Z-score 1.17

OE 0.60 (0.33–1.19)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.06Z-score

OE missense 1.01 (0.90–1.14)

204 obs / 201.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.60 (0.33–1.19)

0≤0.351.4

Missense OE?1.01 (0.90–1.14)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 6 / 10.0Missense obs/exp: 204 / 201.5Syn Z: 0.99

This gene — mechanism propensity

0.73top 25%

GOF

0.84top 5%

LOF

0.2484th %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

66 submitted variants in ClinVar

ClinVar

Classification Summary

VUS58

Likely Benign3

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	58	58
Likely Benign	3	3
Benign	0	0
Total	61	61

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

View in ClinVar →

40 pathogenic / likely-pathogenic (of 48) ClinVar copy-number / structural variants overlap GPR157 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →