GABRA2

Chr 4MultiAD

gamma-aminobutyric acid type A receptor subunit alpha2

Also known as: DEE78, EIEE78

NCBI Gene: 2555ENSG00000151834UniProt: P47869

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. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

Primary Disease Associations & Inheritance

{Alcohol dependence, susceptibility to}MIM #103780
Multi
Developmental and epileptic encephalopathy 78MIM #618557
AD
386
ClinVar variants
39
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— GABRA2
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
39 Pathogenic / Likely Pathogenic· 154 VUS of 386 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.23LOEUF
pLI 0.996
Z-score 4.01
OE 0.05 (0.02–0.23)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
3.13Z-score
OE missense 0.42 (0.36–0.50)
97 obs / 230.7 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.05 (0.02–0.23)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.42 (0.36–0.50)
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.0.93
0≤1.21.6
LoF obs/exp: 1 / 20.7Missense obs/exp: 97 / 230.7Syn Z: 0.49

ClinVar Variant Classifications

386 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24
Likely Pathogenic15
VUS154
Likely Benign161
Benign18
Conflicting14
24
Pathogenic
15
Likely Pathogenic
154
VUS
161
Likely Benign
18
Benign
14
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
4
18
0
24
Likely Pathogenic
0
14
1
0
15
VUS
13
123
16
2
154
Likely Benign
1
35
53
72
161
Benign
0
2
12
4
18
Conflicting
—14
Total1617810078386

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.

Gene2Phenotype Curations

GABRA2-related epileptic encephalopathy

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variant

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Alcohol dependence, susceptibility to}

MIM #103780

Molecular basis of disorder known

Multifactorial

Developmental and epileptic encephalopathy 78

MIM #618557

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genetic variations in GABA metabolism and epilepsy.
Feng Y et al.·Seizure
2022Review
[Posttraumatic stress disorder (PTSD) as a consequence of the interaction between an individual genetic susceptibility, a traumatogenic event and a social context].
Auxéméry Y·Encephale
2012Review
Association of gamma-aminobutyric acid A receptor α2 gene (GABRA2) with alcohol use disorder.
Li D et al.·Neuropsychopharmacology
2014Meta-analysis
Gamma-aminobutyric acid A receptor, α-2 (GABRA2) variants as individual markers for alcoholism: a meta-analysis.
Zintzaras E·Psychiatr Genet
2012Meta-analysis
De novo variants in GABRA2 and GABRA5 alter receptor function and contribute to early-onset epilepsy.
Butler KM et al.·Brain
2018
How phenotype and developmental stage affect the genes we find: GABRA2 and impulsivity.
Dick DM et al.·Twin Res Hum Genet
2013
GABRA2 genotype, impulsivity, and body mass.
Bauer LO et al.·Am J Addict
2012
FRMD7 Mutations Disrupt the Interaction with GABRA2 and May Result in Infantile Nystagmus Syndrome.
Jiang L et al.·Invest Ophthalmol Vis Sci
2020
A GABRA2 variant is associated with increased stimulation and 'high' following alcohol administration.
Arias AJ et al.·Alcohol Alcohol
2014
Structural analysis of pathogenic missense mutations in GABRA2 and identification of a novel de novo variant in the desensitization gate.
Sanchis-Juan A et al.·Mol Genet Genomic Med
2020Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
GABRA2-related encephalopathy: Identification of two phenotypes with distinctive electroclinical features.
Adamo-Croux M et al.·Epilepsia
2025🔓 Open Access
A novel de novo GABRA2 gene missense variant causing developmental epileptic encephalopathy in a Chinese patient.
Yang L et al.·Ann Clin Transl Neurol
2025🔓 Open Access
5,7,3',4',5'-Pentamethoxyflavone, a Flavonoid Monomer Extracted From Murraya paniculata (L.) Jack, Alleviates Anxiety Through the A2AR/Gephyrin/GABRA2 Pathway.
Ma W et al.·Phytother Res
2024
Prospective DNA Methylation Analysis of the CpG GABRA2 Receptor Subunit in Alcohol Dependence during Detoxification.
Preuss UW et al.·Medicina (Kaunas)
2022🔓 Open Access
CYP2A6 and GABRA2 Gene Polymorphisms are Associated With Dexmedetomidine Drug Response.
Fang C et al.·Front Pharmacol
2022🔓 Open Access
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