GABRA3

Chr XX-linked

gamma-aminobutyric acid type A receptor subunit alpha3

Also known as: EPILX2

NCBI Gene: 2556ENSG00000011677UniProt: P34903OMIM: 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).

OMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismX-linkedLOEUF 0.701 OMIM phenotype
Clinical Summary— GABRA3
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.
📋
ClinVar Variants
93 unique Pathogenic / Likely Pathogenic· 60 VUS of 203 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
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 OE0.33 (0.17–0.70)
0≤0.351.4
Missense OE0.49 (0.42–0.58)
0≤0.61.4
Synonymous OE0.90
0≤1.21.6
LoF obs/exp: 5 / 15.0Missense obs/exp: 97 / 196.8Syn Z: 0.68
DN
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

203 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic90
Likely Pathogenic3
VUS60
Likely Benign14
Benign3
90
Pathogenic
3
Likely Pathogenic
60
VUS
14
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
3
87
0
90
Likely Pathogenic
0
1
2
0
3
VUS
3
45
12
0
60
Likely Benign
0
4
4
6
14
Benign
0
0
2
1
3
Total3531077170

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

View in ClinVar →

Protein Context — Lollipop Plot

GABRA3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients