GPR139

Chr 16

G protein-coupled receptor 139

Also known as: GPRg1, PGR3

NCBI Gene: 124274 ENSG00000180269 UniProt: Q6DWJ6 OMIM: 618448

This gene encodes a G-protein-coupled receptor of the rhodopsin family that is almost exclusively expressed in the central nervous system and appears to respond to L-tryptophan and L-phenylalanine through a G(q/11)-mediated pathway. Mutations in GPR139 cause autosomal recessive intellectual disability with seizures and behavioral abnormalities. The gene shows low constraint against loss-of-function variants, consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the rhodopsin family of G-protein-coupled receptors. The encoded protein is almost exclusively expressed in the central nervous system. L-tryptophan and L-phenylalanine may act as the physiologic ligands of the encoded protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.87

Clinical Summary— GPR139

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Population Constraint (gnomAD)

Low constraint (pLI 0.04) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.87LOEUF

pLI 0.037

Z-score 1.87

OE 0.38 (0.19–0.87)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.91Z-score

OE missense 0.82 (0.72–0.93)

166 obs / 202.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.38 (0.19–0.87)

0≤0.351.4

Missense OE?0.82 (0.72–0.93)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 4 / 10.6Missense obs/exp: 166 / 202.5Syn Z: -0.43

This gene — mechanism propensity

0.7132th %ile

GOF

0.80top 10%

LOF

0.2581th %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.