GABRA5

Chr 15AD

gamma-aminobutyric acid type A receptor subunit alpha5

Also known as: DEE79, EIEE79

NCBI Gene: 2558ENSG00000186297UniProt: P31644OMIM: 137142

The protein encoded by this gene forms part of GABA-A receptors, which are ligand-gated chloride channels that mediate the major inhibitory neurotransmission in the brain. Mutations cause developmental and epileptic encephalopathy 79 through an autosomal dominant inheritance pattern via a gain-of-function mechanism. The gene is highly constrained against loss-of-function variants, consistent with the pathogenic mechanism being gain-of-function rather than haploinsufficiency.

OMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
MultiplemechanismADLOEUF 0.371 OMIM phenotype
Clinical Summary— GABRA5
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.91). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
310 unique Pathogenic / Likely Pathogenic· 80 VUS of 442 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
0.37LOEUF
pLI 0.905
Z-score 3.62
OE 0.14 (0.07–0.37)
Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
3.23Z-score
OE missense 0.46 (0.39–0.53)
127 obs / 278.8 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.14 (0.07–0.37)
0≤0.351.4
Missense OE0.46 (0.39–0.53)
0≤0.61.4
Synonymous OE1.03
0≤1.21.6
LoF obs/exp: 3 / 20.8Missense obs/exp: 127 / 278.8Syn Z: -0.25
DN
0.6937th %ile
GOF
0.75top 25%
LOF
0.4430th %ile

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.

DNprediction above median · 1 literature citation
GOFprediction above median
LOFLOEUF 0.37

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

DNFurthermore, mutant a5(S413F)HA subunits had a dominant negative effect by decreasing the trafficking of partnering b3 (0.65 ± 0.06, P = 0.0003, n = 4) and g2 (0.65 ± 0.06, P = 0.0106, n = 4) subunits to the surface (Fig. 3C, middle and bottom). Mutant a5(S413F)HA subunits had a dominant negative efPMID:31056671

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

442 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic300
Likely Pathogenic10
VUS80
Likely Benign37
Benign12
Conflicting1
300
Pathogenic
10
Likely Pathogenic
80
VUS
37
Likely Benign
12
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
3
297
0
300
Likely Pathogenic
0
2
8
0
10
VUS
5
64
10
1
80
Likely Benign
0
6
5
26
37
Benign
0
1
5
6
12
Conflicting
—1
Total57632533440

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

View in ClinVar →

Protein Context — Lollipop Plot

GABRA5 · 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
Potential mechanism of the Shunaoxin pill for preventing cognitive impairment in type 2 diabetes mellitus
Guo Y et al.·Front Neurol
2022Functional
Author Correction: Hypothalamic GABRA5-positive neurons control obesity via astrocytic GABA.
Sa M et al.·Nat Metab
2023
Synthesis and evaluation of a novel inhibitor for the alpha5-GABAA receptor in the treatment of peripheral neuralgia: Evidence from MD simulation and in vivo studies.
Chen Y et al.·Br J Pharmacol
2025
Plasma EAAT2 and GABA as candidate biomarkers in males with autism spectrum disorder: an exploratory case-control study with ROC analysis.
El-Ansary A et al.·Sci Rep
2026
Comparative evaluation of certain biomarkers emphasizing abnormal GABA inhibitory effect and glutamate excitotoxicity in autism spectrum disorders
Alabdali A et al.·Front Psychiatry
2025
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