GPR156

Chr 3AR

G protein-coupled receptor 156

ENSG00000175697 UniProt: Q8NFN8 OMIM: 610464

This orphan G-protein coupled receptor regulates hair cell orientation in the inner ear mechanosensory organs, specifically triggering 180-degree reversals in hair cell polarity to create the line of polarity reversal across which stereociliary bundles are arranged in opposite orientations. Mutations cause autosomal recessive deafness, typically presenting as congenital hearing loss. The gene shows very low constraint against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

Orphan G protein-coupled receptor involved in the regulation of hair cell orientation in mechanosensory organs of the inner ear. It is required to trigger a 180 degree reversal in hair cell orientation, creating a virtual line of polarity reversal (LPR) across which stereociliary bundles are arranged in opposite orientations

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.031 OMIM phenotype

Clinical Summary— GPR156

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.03LOEUF

pLI 0.000

Z-score 1.40

OE 0.73 (0.52–1.03)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.04Z-score

OE missense 0.86 (0.79–0.94)

382 obs / 443.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.73 (0.52–1.03)

0≤0.351.4

Missense OE?0.86 (0.79–0.94)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 23 / 31.5Missense obs/exp: 382 / 443.6Syn Z: 0.63

This gene — mechanism propensity

0.7033th %ile

GOF

0.74top 25%

LOF

0.3745th %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.