GPR156

Chr 3AR

G protein-coupled receptor 156

Also known as: DFNB121, GABABL, PGR28

NCBI Gene: 165829 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

G protein-coupled receptors (GPCRs) are a large superfamily of cell surface receptors characterized by 7 helical transmembrane domains, together with N-terminal extracellular and C-terminal intracellular domains.[supplied by OMIM, Mar 2008]

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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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 112 VUS of 138 total submissions

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?

1.03LOEUF

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.

ClinVar Variant Classifications

138 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic5

VUS112

Likely Benign14

Likely Pathogenic

112

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	4	0	1	5
VUS	0	112	0	112
Likely Benign	0	12	2	14
Benign	0	0	0	0
Total	4	124	3	131

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap GPR156 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →