GPRC5B

Chr 16AD

G protein-coupled receptor class C group 5 member B

Also known as: MLC3, RAIG-2, RAIG2

NCBI Gene: 51704 ENSG00000167191 UniProt: Q9NZH0 OMIM: 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the type 3 G protein-coupled receptor family. Members of this superfamily are characterized by a signature 7-transmembrane domain motif. The encoded protein may modulate insulin secretion and increased protein expression is associated with type 2 diabetes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.771 OMIM phenotype

Clinical Summary— GPRC5B

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Population Constraint (gnomAD)

Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 61 VUS of 81 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GPRC5B

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.77LOEUF

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 OE?0.36 (0.19–0.77)

0≤0.351.4

Missense OE?0.77 (0.68–0.86)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 5 / 13.7Missense obs/exp: 200 / 260.1Syn Z: -0.72

This gene — mechanism propensity

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

81 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS61

Likely Benign7

Benign3

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	2	0	2
Likely Pathogenic	0	0	0
VUS	61	0	61
Likely Benign	2	5	7
Benign	2	1	3
Total	67	6	73

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap GPRC5B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →