GPRC5B

Chr 16AD

G protein-coupled receptor class C group 5 member B

Also known as: MLC3, RAIG-2, RAIG2

NCBI Gene: 51704ENSG00000167191UniProt: Q9NZH0OMIM: 605948

The protein is a G-protein coupled receptor that regulates cell volume and may modulate insulin secretion. Mutations cause megalencephalic leukoencephalopathy with subcortical cysts 3, a white matter disorder affecting the brain. The condition follows autosomal dominant inheritance.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismADLOEUF 0.771 OMIM phenotype
Clinical Summary— GPRC5B
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
16 unique Pathogenic / Likely Pathogenic· 63 VUS of 97 total submissions
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — GPRC5B
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.77LOEUF
pLI 0.024
Z-score 2.19
OE 0.36 (0.19–0.77)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
1.32Z-score
OE missense 0.77 (0.68–0.86)
200 obs / 260.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.36 (0.19–0.77)
0≤0.351.4
Missense OE0.77 (0.68–0.86)
0≤0.61.4
Synonymous OE1.08
0≤1.21.6
LoF obs/exp: 5 / 13.7Missense obs/exp: 200 / 260.1Syn Z: -0.72
DN
0.6745th %ile
GOF
0.77top 25%
LOF
0.3068th %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

97 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16
VUS63
Likely Benign7
Benign3
16
Pathogenic
63
VUS
7
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
14
0
16
Likely Pathogenic
0
0
0
0
0
VUS
0
60
3
0
63
Likely Benign
0
2
0
5
7
Benign
0
2
0
1
3
Total06617689

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

View in ClinVar →

Protein Context — Lollipop Plot

GPRC5B · 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
Aquaporin-4 and GPRC5B: old and new players in controlling brain oedema.
Passchier EMJ et al.·Brain
2023
A Reflux Linked GATA Factor Fulcrum Dictates Lineage Commitment Through GPRC5B During the Esophageal Dysplastic Transition.
Abuhussein O et al.·Cell Mol Gastroenterol Hepatol
2025
Regulation of the orphan G-protein-coupled receptor GPRC5B by MLC1 and the cell adhesion molecule GlialCAM in megalencephalic leukoencephalopathy.
Pont-Espinós G et al.·J Biol Chem
2026
From clinical evidence to biological mechanisms: GPRC5B as a key mediator of metabolic syndrome-associated prostate cancer.
Lin W et al.·Int J Biol Macromol
2026Functional
A Risk Model for Prognosis and Treatment Response Prediction in Colon Adenocarcinoma Based on Genes Associated with the Characteristics of the Epithelial-Mesenchymal Transition.
Huang H et al.·Int J Mol Sci
2023Functional
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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