GPR146

Chr 7

G protein-coupled receptor 146

Also known as: PGR8

NCBI Gene: 115330 ENSG00000164849 UniProt: Q96CH1 OMIM: 621173

GPR146 encodes a G-protein coupled receptor that regulates plasma cholesterol levels by binding the gut hormone cholesin, which inhibits hepatic cholesterol synthesis in response to intestinal cholesterol absorption. Mutations cause autosomal recessive familial hypercholesterolemia, presenting with elevated cholesterol levels and increased cardiovascular risk. The gene shows tolerance to loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.06

Clinical Summary— GPR146

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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?

1.06LOEUF

pLI 0.149

Z-score 1.50

OE 0.34 (0.14–1.06)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.42Z-score

OE missense 1.08 (0.97–1.20)

244 obs / 226.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.34 (0.14–1.06)

0≤0.351.4

Missense OE?1.08 (0.97–1.20)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 2 / 5.9Missense obs/exp: 244 / 226.3Syn Z: -1.50

This gene — mechanism propensity

0.6261th %ile

GOF

0.76top 25%

LOF

0.2776th %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.