GABRA3

Chr XX-linked

gamma-aminobutyric acid type A receptor subunit alpha3

Also known as: EPILX2

NCBI Gene: 2556 ENSG00000011677 UniProt: P34903 OMIM: 305660

The protein functions as an alpha subunit of GABA-A receptors, heteropentameric ligand-gated chloride channels that mediate inhibitory neurotransmission in the brain by allowing chloride influx when activated by GABA. Mutations cause X-linked epilepsy with or without intellectual disability and dysmorphic features, following X-linked inheritance. The gene shows relatively low constraint to loss-of-function variation (pLI 0.04, LOEUF 0.70).

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. At least 16 distinct subunits of GABA-A receptors have been identified. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismX-linkedLOEUF 0.701 OMIM phenotype

Clinical Summary— GABRA3

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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ClinVar Variants

4 unique Pathogenic / Likely Pathogenic· 52 VUS of 107 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GABRA3

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?

0.70LOEUF

pLI 0.039

Z-score 2.40

OE 0.33 (0.17–0.70)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.53Z-score

OE missense 0.49 (0.42–0.58)

97 obs / 196.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.33 (0.17–0.70)

0≤0.351.4

Missense OE?0.49 (0.42–0.58)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 5 / 15.0Missense obs/exp: 97 / 196.8Syn Z: 0.68

This gene — mechanism propensity

0.82top 10%

GOF

0.80top 10%

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

107 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic1

VUS52

Likely Benign15

Benign3

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	3	0	0	3
Likely Pathogenic	0	1	0	0	1
VUS	3	46	3	0	52
Likely Benign	0	5	4	6	15
Benign	0	0	2	1	3
Total	3	55	9	7	74

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

View in ClinVar →

95 pathogenic / likely-pathogenic (of 104) ClinVar copy-number / structural variants overlap GABRA3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →