GABRG2
Chr 5ADgamma-aminobutyric acid type A receptor subunit gamma2
Also known as: CAE2, DEE74, ECA2, EIEE74, FEB8, GEFSP3
The gene encodes the gamma-2 subunit of GABA-A receptors, which are pentameric ligand-gated chloride channels that mediate inhibitory neurotransmission in the brain. Mutations cause autosomal dominant epilepsy syndromes including developmental and epileptic encephalopathy, generalized epilepsy with febrile seizures plus, and familial febrile seizures. Disease can result from multiple mechanisms depending on the specific variant, with some mutations causing loss of receptor function while others may produce dominant-negative or gain-of-function effects.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Moderately missense-constrained (top ~2.5%)
GABA-A receptor gamma-2 subunit forms pentameric channels. Most pathogenic truncating mutations produce stable mutant proteins with dominant-negative effects on channel assembly. Missense variants reduce surface expression or channel function (LOF). Both LOF and DN mechanisms are established; GOF is not the primary mechanism despite Badonyi prediction.
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports dominant-negative. 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
500 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 | 29 | 5 | 19 | 0 | 53 |
Likely Pathogenic | 21 | 16 | 5 | 0 | 42 |
VUS | 10 | 195 | 33 | 4 | 242 |
Likely Benign | 0 | 7 | 60 | 72 | 139 |
Benign | 0 | 1 | 5 | 0 | 6 |
Conflicting | — | 12 | |||
| Total | 60 | 224 | 122 | 76 | 494 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
GABRG2 · 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
External Resources
Links to major genomics databases and tools