GABRA2
Chr 4MultiADgamma-aminobutyric acid type A receptor subunit alpha2
Also known as: DEE78, EIEE78
The GABRA2 gene encodes the alpha-2 subunit of GABA-A receptors, which are ligand-gated chloride channels that mediate inhibitory neurotransmission in the brain. Pathogenic variants cause developmental and epileptic encephalopathy 78 through autosomal dominant inheritance, likely due to disrupted GABAergic inhibition. The gene shows extreme intolerance to loss-of-function variants (pLI 0.996, LOEUF 0.229), consistent with dominant negative or haploinsufficiency mechanisms.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Highly missense-constrained (top ~0.1%)
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
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.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
392 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 2 | 4 | 18 | 0 | 24 |
Likely Pathogenic | 0 | 14 | 1 | 0 | 15 |
VUS | 21 | 123 | 9 | 2 | 155 |
Likely Benign | 3 | 35 | 53 | 71 | 162 |
Benign | 0 | 2 | 12 | 4 | 18 |
Conflicting | — | 14 | |||
| Total | 26 | 178 | 93 | 77 | 388 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
GABRA2 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools