GABRA1

Chr 5AD

gamma-aminobutyric acid type A receptor subunit alpha1

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

NCBI Gene: 2554 ENSG00000022355 UniProt: P14867 OMIM: 137160

The protein functions as the alpha-1 subunit of GABA-A receptors, heteropentameric ligand-gated chloride channels that mediate inhibitory neurotransmission in the brain. Mutations cause developmental and epileptic encephalopathy 19, childhood absence epilepsy, and juvenile myoclonic epilepsy through an autosomal dominant inheritance pattern. Disease mechanisms are variant-dependent, with mutations causing pathogenicity through either loss-of-function or dominant-negative effects.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

LOF/DNmechanismADLOEUF 0.373 OMIM phenotypes

Clinical Summary— GABRA1

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Gene-Disease Validity (ClinGen)

epilepsy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

82 unique Pathogenic / Likely Pathogenic· 346 VUS of 788 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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 0.915

Z-score 3.65

OE 0.14 (0.06–0.37)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

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?

LoF OE?0.14 (0.06–0.37)

0≤0.351.4

Missense OE?0.43 (0.37–0.51)

0≤0.61.4

Synonymous OE?1.25

0≤1.21.6

LoF obs/exp: 3 / 21.1Missense obs/exp: 105 / 243.2Syn Z: -1.91

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongGABRA1-related epileptic encephalopathyOTHERAD

strongGABRA1-related juvenile myoclonic epilepsyLOFAD

Mechanism Note (variant-dependent)

LOFDN— mechanism depends on specific variant

GABA-A receptor alpha-1 subunit. Truncating variants cause haploinsufficiency (LOF) leading to DEE. Some missense variants cause dominant-negative effects on pentameric assembly. GOF is not an established mechanism.1

This gene — mechanism propensity

0.6259th %ile

GOF

0.72top 25%

LOF

0.50top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-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 loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 17% of P/LP variants are LoF · LOEUF 0.37

DNprediction above median · 1 literature citation

GOFprediction above median · 76% of P/LP are missense

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

DNThese findings demonstrated that, in addition to causing a heterozygous loss of function of alpha1(AD) subunits, this epilepsy mutation also elicited a modest dominant negative effect that likely shapes the epilepsy phenotype.2

LOFWe conclude that this de novo mutation can contribute to the cause of """"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""sporadic"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""" childhood absence epilepsy by a loss of function and haploinsufficiency of the GABA(A) recept3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

788 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic42

Likely Pathogenic40

VUS346

Likely Benign239

Benign47

Conflicting74

Pathogenic

Likely Pathogenic

346

VUS

239

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	26	5	0	42
Likely Pathogenic	3	36	1	0	40
VUS	14	251	77	4	346
Likely Benign	0	8	108	123	239
Benign	0	8	36	3	47
Conflicting	—				74
Total	28	329	227	130	788

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap GABRA1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →