GABRA3

Chr XX-linked

gamma-aminobutyric acid type A receptor subunit alpha3

Also known as: EPILX2

NCBI Gene: 2556ENSG00000011677UniProt: P34903

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]

Primary Disease Associations & Inheritance

Epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic featuresMIM #301091
X-linked
303
ClinVar variants
93
Pathogenic / LP
0.04
pLI score
0
Active trials
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 Pathogenic / Likely Pathogenic· 60 VUS of 303 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.70LOEUF
pLI 0.039
Z-score 2.40
OE 0.33 (0.17–0.70)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.33 (0.17–0.70)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.49 (0.42–0.58)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.90
0≤1.21.6
LoF obs/exp: 5 / 15.0Missense obs/exp: 97 / 196.8Syn Z: 0.68

ClinVar Variant Classifications

303 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
1
45
14
0
60
Likely Benign
0
4
4
6
14
Benign
0
0
2
1
3
Total1531097170

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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features

MIM #301091

Molecular basis of disorder known

X-linked
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Functional consequence of pathogenic GABRA3 variants determines whether X-linked inheritance is dominant or recessive.
Johannesen KM et al.·J Clin Invest
2025Functional
Whole exome sequencing revealed ultra-rare genetic variations in juvenile myoclonic epilepsy.
Yacoub AM et al.·Neurol Sci
2025
Long-term treatment with benzodiazepines and related Z-drugs exacerbates breast cancer: clinical evidence and molecular mechanisms.
Yang WV et al.·Cell Mol Biol Lett
2025Functional
Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features.
Niturad CE et al.·Brain
2017
miR-92b-3p acts as a tumor suppressor by targeting Gabra3 in pancreatic cancer.
Long M et al.·Mol Cancer
2017
MiR-92b inhibited cells EMT by targeting Gabra3 and predicted prognosis of triple negative breast cancer patients.
Li YY et al.·Eur Rev Med Pharmacol Sci
2019Cohort
Unraveling the role of miR-767 in tumor progression: Mechanisms and clinical implications.
Fu Z et al.·Gene
2025Review
Mutation screening in Rett syndrome patients.
Xiang F et al.·J Med Genet
2000Cohort
Age-related gene-specific changes of A-to-I mRNA editing in the human brain.
Nicholas A et al.·Mech Ageing Dev
2010
Genomically Complex Human Angiosarcoma and Canine Hemangiosarcoma Establish Convergent Angiogenic Transcriptional Programs Driven by Novel Gene Fusions.
Kim JH et al.·Mol Cancer Res
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools