GABRA4

Chr 4

gamma-aminobutyric acid type A receptor subunit alpha4

NCBI Gene: 2557 ENSG00000109158 UniProt: P48169 OMIM: 137141

The GABRA4 protein forms the alpha-4 subunit of GABA-A receptors, heteropentameric chloride channels that mediate inhibitory neurotransmission in the brain, with alpha-4-containing receptors predominantly located extrasynaptically where they provide tonic inhibition. Mutations in GABRA4 have been associated with autism spectrum disorders, following autosomal dominant inheritance. The gene shows high constraint against loss-of-function variants (LOEUF 0.41), indicating that such variants are likely to be pathogenic when they occur.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.41

Clinical Summary— GABRA4

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.78) — some intolerance to loss-of-function variants.

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ClinVar Variants

56 VUS of 75 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

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?

LoF OE?0.18 (0.09–0.41)

0≤0.351.4

Missense OE?0.68 (0.60–0.76)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 4 / 22.6Missense obs/exp: 208 / 306.8Syn Z: -1.64

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateGABRA4-related neurodevelopmental disorder with seizuresOTHERAD

This gene — mechanism propensity

0.7229th %ile

GOF

0.77top 25%

LOF

0.4529th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

75 submitted variants in ClinVar

ClinVar

Classification Summary

VUS56

Likely Benign10

Benign4

Conflicting1

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	54	1	0	56
Likely Benign	0	6	1	3	10
Benign	0	1	1	2	4
Conflicting	—				1
Total	1	61	3	5	71

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap GABRA4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →