GABRA1

Chr 5AD

gamma-aminobutyric acid type A receptor subunit alpha1

Also known as: DEE19, ECA4, EIEE19, EJM, EJM5

NCBI Gene: 2554ENSG00000022355UniProt: P14867

This gene encodes a gamma-aminobutyric acid (GABA) receptor. 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. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene cause juvenile myoclonic epilepsy and childhood absence epilepsy type 4. Multiple transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

{Epilepsy, childhood absence, susceptibility to, 4}MIM #611136
{Epilepsy, juvenile myoclonic, susceptibility to, 5}MIM #611136
Developmental and epileptic encephalopathy 19MIM #615744
AD
UniProtEpilepsy, idiopathic generalized 13
499
ClinVar variants
59
Pathogenic / LP
0.91
pLI score· haploinsufficient
1
Active trials
Clinical Summary— GABRA1
🧬
Gene-Disease Validity (ClinGen)
epilepsy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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
59 Pathogenic / Likely Pathogenic· 209 VUS of 499 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

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.
0.37LOEUF
pLI 0.915
Z-score 3.65
OE 0.14 (0.06–0.37)
Highly constrained

More LoF-intolerant than ~75% 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.
3.15Z-score
OE missense 0.43 (0.37–0.51)
105 obs / 243.2 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.0.14 (0.06–0.37)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.43 (0.37–0.51)
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.1.25
0≤1.21.6
LoF obs/exp: 3 / 21.1Missense obs/exp: 105 / 243.2Syn Z: -1.91

ClinVar Variant Classifications

499 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33
Likely Pathogenic26
VUS209
Likely Benign176
Benign27
Conflicting28
33
Pathogenic
26
Likely Pathogenic
209
VUS
176
Likely Benign
27
Benign
28
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
16
13
0
33
Likely Pathogenic
2
21
3
0
26
VUS
5
175
28
1
209
Likely Benign
0
6
81
89
176
Benign
0
7
20
0
27
Conflicting
—28
Total1122514590499

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

View in ClinVar →

Protein Context — Lollipop Plot

GABRA1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

GABRA1-related epileptic encephalopathy

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

GABRA1-related juvenile myoclonic epilepsy

strong
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Epilepsy, childhood absence, susceptibility to, 4}

MIM #611136

Molecular basis of disorder known

{Epilepsy, juvenile myoclonic, susceptibility to, 5}

MIM #611136

Molecular basis of disorder known

Developmental and epileptic encephalopathy 19

MIM #615744

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — GABRA1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
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
Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders.
Lindy AS et al.·Epilepsia
2018Cohort
Molecular and clinical descriptions of patients with GABA(A) receptor gene variants (GABRA1, GABRB2, GABRB3, GABRG2): A cohort study, review of literature, and genotype-phenotype correlation.
Maillard PY et al.·Epilepsia
2022Review
The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures.
Burgess R et al.·Ann Neurol
2019
Unraveling the genetic basis of epilepsy: Recent advances and implications for diagnosis and treatment.
Dwivedi R et al.·Brain Res
2024Review
Genetics of epilepsy.
Nolan D et al.·Handb Clin Neurol
2018Review
Understanding paralogous epilepsy-associated GABA(A) receptor variants: Clinical implications, mechanisms, and potential pitfalls.
Kan ASH et al.·Proc Natl Acad Sci U S A
2024Functional
Genetic Causes of Generalized Epilepsies.
Helbig I·Semin Neurol
2015Review
Epilepsy plus blindness in microdeletion of GABRA1 and GABRG2 in mouse and human.
Zhang Q et al.·Exp Neurol
2023Functional
Pathophysiology of and therapeutic options for a GABRA1 variant linked to epileptic encephalopathy.
Bai YF et al.·Mol Brain
2019
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Porcine Cardiac Blood processed Kansui Radix alleviates PTZ-induced epileptic damage in mice via the bidirectional regulation of GABRA1 and cGMP/PKG signaling pathway.
Cai J et al.·J Ethnopharmacol
2026
Characterization of the zebrafish gabra1sa43718/sa43718 germline loss of function allele confirms a function for Gabra1 in motility and nervous system development.
Reyes-Nava NG et al.·Differentiation
2024Functional
Association between Genetic Polymorphism of SCN1A, GABRA1 and ABCB1 and Drug Responsiveness in Vietnamese Epileptic Children.
Tang HX et al.·Medicina (Kaunas)
2024🔓 Open Access
De novo GABRA1 variants in childhood epilepsies and the molecular subregional effects.
Liu WH et al.·Front Mol Neurosci
2023🔓 Open Access
Pathogenic variants of human GABRA1 gene associated with epilepsy: A computational approach.
Arslan A.·Heliyon
2023🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Epilepsy

Precision Medicine in the Treatment of Epilepsy

RECRUITING
NCT05450822Gitte Moos KnudsenStarted 2022-02-18
LevetiracetamLevetiracetam TabletsLamotrigine tablet

External Resources

Links to major genomics databases and tools