GAS2

Chr 11

growth arrest specific 2

Also known as: DFNB125, GAS-2

NCBI Gene: 2620 ENSG00000148935 UniProt: O43903

The GAS2 protein is required to maintain microtubule bundles in inner ear supporting cells, providing mechanical stiffness necessary for sound transmission through the cochlea. Mutations cause autosomal recessive nonsyndromic hearing loss, with this gene being relatively tolerant to loss-of-function variants based on population constraint metrics. A GeneReviews entry is available for additional clinical guidance.

GeneReviews ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a caspase-3 substrate that plays a role in regulating microfilament and cell shape changes during apoptosis. It can also modulate cell susceptibility to p53-dependent apoptosis by inhibiting calpain activity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2017]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.81

Clinical Summary— GAS2

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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

2 unique Pathogenic / Likely Pathogenic· 31 VUS of 44 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GAS2

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.001

Z-score 2.15

OE 0.45 (0.26–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.44Z-score

OE missense 0.91 (0.79–1.03)

154 obs / 170.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.45 (0.26–0.81)

0≤0.351.4

Missense OE?0.91 (0.79–1.03)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 8 / 17.8Missense obs/exp: 154 / 170.2Syn Z: 0.16

This gene — mechanism propensity

0.7035th %ile

GOF

0.6541th %ile

LOF

0.2679th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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

44 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS31

Benign3

Pathogenic

Likely Pathogenic

VUS

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	0	1	0	0	1
VUS	0	31	0	0	31
Likely Benign	0	0	0	0	0
Benign	0	0	2	1	3
Total	1	32	2	1	36

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 40) ClinVar copy-number / structural variants overlap GAS2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →