GPR139

Chr 16

G protein-coupled receptor 139

Also known as: GPRg1, PGR3

NCBI Gene: 124274ENSG00000180269UniProt: Q6DWJ6OMIM: 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.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 0.87
Clinical Summary— GPR139
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.04) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
14 unique Pathogenic / Likely Pathogenic· 41 VUS of 57 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
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 OE0.38 (0.19–0.87)
0≤0.351.4
Missense OE0.82 (0.72–0.93)
0≤0.61.4
Synonymous OE1.06
0≤1.21.6
LoF obs/exp: 4 / 10.6Missense obs/exp: 166 / 202.5Syn Z: -0.43
DN
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.

ClinVar Variant Classifications

57 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14
VUS41
Likely Benign1
14
Pathogenic
41
VUS
1
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
14
0
14
Likely Pathogenic
0
0
0
0
0
VUS
0
37
4
0
41
Likely Benign
0
1
0
0
1
Benign
0
0
0
0
0
Total03818056

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

View in ClinVar →

Protein Context — Lollipop Plot

GPR139 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
GPR139, an Ancient Receptor and an Emerging Target for Neuropsychiatric and Behavioral Disorders.
Chan M et al.·Mol Neurobiol
2025Review
Discovery of TAK-041: a Potent and Selective GPR139 Agonist Explored for the Treatment of Negative Symptoms Associated with Schizophrenia.
Reichard HA et al.·J Med Chem
2021
Single-nuclei and bulk-tissue gene-expression analysis of pheochromocytoma and paraganglioma links disease subtypes with tumor microenvironment.
Zethoven M et al.·Nat Commun
2022
Molecular insights into orphan G protein-coupled receptors relevant to schizophrenia.
Lu Y et al.·Br J Pharmacol
2024Review
Identification of key genes involved in the recurrence of glioblastoma multiforme using weighted gene co-expression network analysis and differential expression analysis.
Ren P et al.·Bioengineered
2021
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Expression Analysis of the orphan receptors GPR161, GPR132, GPR20, and GPR139 in patients with cervicitis and low-grade, and high-grade squamous intraepithelial lesions.
Rodríguez JE et al.·Genet Mol Biol
2026Open AccessCohort
Ultra-large virtual screening unveils potent agonists of the neuromodulatory orphan receptor GPR139.
Cabeza de Vaca I et al.·Nat Commun
2025Open Access
The GPR139 agonist TAK-041 produces time-dependent alterations to cerebral blood flow and reward system function in patients with schizophrenia: a randomised placebo-controlled trial.
Hawkins PCT et al.·Psychopharmacology (Berl)
2026Open AccessCohort
Correction to "Surrogate GPR139 Agonists Reverse Short-Term Startle Habituation Impairment in Larval Zebrafish".
·FASEB J
2025Functional
Surrogate GPR139 Agonists Reverse Short-Term Startle Habituation Impairment in Larval Zebrafish.
Kow TF et al.·FASEB J
2025Open AccessFunctional
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients