GABRA4

Chr 4

gamma-aminobutyric acid type A receptor subunit alpha4

NCBI Gene: 2557ENSG00000109158UniProt: P48169

Gamma-aminobutyric acid (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. This gene encodes subunit alpha-4, which is involved in the etiology of autism and eventually increases autism risk through interaction with another subunit, gamma-aminobutyric acid receptor beta-1 (GABRB1). Alternatively spliced transcript variants encoding different isoforms have been found in this gene.[provided by RefSeq, Feb 2011]

91
ClinVar variants
19
Pathogenic / LP
0.78
pLI score
0
Active trials
Clinical Summary— GABRA4
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.78) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
19 Pathogenic / Likely Pathogenic· 57 VUS of 91 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.41LOEUF
pLI 0.779
Z-score 3.62
OE 0.18 (0.09–0.41)
Moderately 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.
2.00Z-score
OE missense 0.68 (0.60–0.76)
208 obs / 306.8 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.18 (0.09–0.41)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.68 (0.60–0.76)
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.1.20
0≤1.21.6
LoF obs/exp: 4 / 22.6Missense obs/exp: 208 / 306.8Syn Z: -1.64

ClinVar Variant Classifications

91 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18
Likely Pathogenic1
VUS57
Likely Benign10
Benign4
Conflicting1
18
Pathogenic
1
Likely Pathogenic
57
VUS
10
Likely Benign
4
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
18
0
18
Likely Pathogenic
0
0
1
0
1
VUS
1
53
3
0
57
Likely Benign
0
6
1
3
10
Benign
0
1
1
2
4
Conflicting
—1
Total16024591

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

View in ClinVar →

Protein Context — Lollipop Plot

GABRA4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

GABRA4-related neurodevelopmental disorder with seizures

moderate
ADUndetermined Non-Loss-Of-FunctionAltered 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
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A de novo missense variant in GABRA4 alters receptor function in an epileptic and neurodevelopmental phenotype.
Vogel FD et al.·Epilepsia
2022
Gamma-aminobutyric acid GABRA4, GABRE, and GABRQ receptor polymorphisms and risk for essential tremor.
García-Martín E et al.·Pharmacogenet Genomics
2011
De novo variants in GABRA4 are associated with a neurological phenotype including developmental delay, behavioral abnormalities and epilepsy.
Sajan SA et al.·Eur J Hum Genet
2024Case report
Disrupted synaptic gene expression in Fabry disease: Findings from RNA sequencing.
López-Valverde L et al.·Neurobiol Dis
2025
Further evidence of GABRA4 and TOP3B as autism susceptibility genes.
Riley JD et al.·Eur J Med Genet
2020Case report
The de novo GABRA4 p.Thr300Ile variant found in a patient with early-onset intractable epilepsy and neurodevelopmental abnormalities displays gain-of-function traits.
Ahring PK et al.·Epilepsia
2022
Lung Cancer in Ever- and Never-Smokers: Findings from Multi-Population GWAS Studies.
Li Y et al.·Cancer Epidemiol Biomarkers Prev
2024
Gamma-aminobutyric acid (GABA) receptors genes polymorphisms and risk for restless legs syndrome.
Jiménez-Jiménez FJ et al.·Pharmacogenomics J
2018
Genetic Association Study of Restless Legs Syndrome in Chinese Population.
Chen J et al.·Eur Neurol
2019
Resident intruder paradigm-induced PMDD rat model of premenstrual irritability: behavioral phenotypes, drug intervention, and biomarkers.
Gao M et al.·Aging (Albany NY)
2022Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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