GPR146

Chr 7

G protein-coupled receptor 146

Also known as: PGR8

NCBI Gene: 115330ENSG00000164849UniProt: Q96CH1

Enables G protein-coupled receptor activity. Involved in adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway and regulation of cholesterol biosynthetic process. Is active in plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

62
ClinVar variants
39
Pathogenic / LP
0.15
pLI score
1
Active trials
Clinical Summary— GPR146
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.
📋
ClinVar Variants
39 Pathogenic / Likely Pathogenic· 16 VUS of 62 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.06LOEUF
pLI 0.149
Z-score 1.50
OE 0.34 (0.14–1.06)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.42Z-score
OE missense 1.08 (0.97–1.20)
244 obs / 226.3 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.34 (0.14–1.06)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.08 (0.97–1.20)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.18
0≤1.21.6
LoF obs/exp: 2 / 5.9Missense obs/exp: 244 / 226.3Syn Z: -1.50

ClinVar Variant Classifications

62 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38
Likely Pathogenic1
VUS16
Likely Benign5
Benign2
38
Pathogenic
1
Likely Pathogenic
16
VUS
5
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories· variant type breakdown unavailable

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
————38
Likely Pathogenic
————1
VUS
————16
Likely Benign
————5
Benign
————2
Total—62

Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

GPR146 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A study into rare GPR146 gene variants in humans and mice.
Zhang B et al.·Atherosclerosis
2025
Targeting orphan G protein-coupled receptors for the treatment of diabetes and its complications: C-peptide and GPR146.
Kolar GR et al.·J Intern Med
2017Review
Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile.
Rimbert A et al.·Arterioscler Thromb Vasc Biol
2022
Cholesin receptor signalling is active in cardiovascular system-associated adipose tissue and correlates with SGLT2i treatment in patients with diabetes.
Ryk A et al.·Cardiovasc Diabetol
2024Cohort
Loss of GPR146 decreases plasma levels of HDL cholesterol via post-translational up-regulation of SR-B1 protein levels.
Zhang B et al.·Cardiovasc Res
2026
Cholesin mRNA Expression in Human Intestinal, Liver, and Adipose Tissues.
Gilliam-Vigh H et al.·Nutrients
2025
From Genetic Findings to new Intestinal Molecular Targets in Lipid Metabolism.
Le May C et al.·Curr Atheroscler Rep
2025Review
Construction of store-operated calcium entry-related gene signature for predicting prognosis and indicates immune microenvironment infiltration in stomach adenocarcinomas.
Zhang Z et al.·Sci Rep
2024
Combined signature of G protein-coupled receptors and tumor microenvironment provides a prognostic and therapeutic biomarker for skin cutaneous melanoma.
Song B et al.·J Cancer Res Clin Oncol
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Healthy Participants

GPR146 and Cholesterol Metabolism

NOT YET RECRUITING
NCT07142317Phase NAMaastricht University Medical CenterStarted 2025-10
Cholesterol-poor, plant sterol-poor shakeCholesterol-rich, plant sterol-poor shakeCholesterol-rich, plant sterol-rich shake

External Resources

Links to major genomics databases and tools