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.

GeneReviews 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]

GeneReviews OMIM ResearchGenerating clinical summary…

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

UniProtEpilepsy, idiopathic generalized 13

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · epilepsy · AD · ClinGen 2024
Definitive · developmental and epileptic encephalopathy, 19 · AD · Ambry Genetics
Strong · epilepsy, idiopathic generalized, susceptibility to, 13 · AD · G2P
Supportive · juvenile myoclonic epilepsy · AD · Orphanet

+1 more curated pair

Interpreting a novel variant

Both loss of function and dominant negative mechanisms are described for this gene and which one applies is variant-dependent. Do not assume a null variant is — or isn't — the pathogenic class without checking the specific variant against curated evidence.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.37

LOEUF

LOF/DN*

Mechanism· annotated

📖

GeneReview available — GABRA1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Background carrier burden — how many people carry a rare variant somewhere in GABRA1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 400

331 rare PASS variants

Rare truncating (LoF)

1 in 13,000

27 rare PASS variants

Rare synonymous (reference)

1 in 130

234 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GABRA1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 560	1 in 12,000
South Asian	~43k	1 in 310	none seen
Remaining (unassigned)	~30k	1 in 290	none seen
European (Finnish)	~27k	1 in 360	none seen
Admixed American	~22k	1 in 410	none seen
African / African American	~21k	1 in 380	≈ 1 in 4,500
East Asian	~20k	1 in 290	1 in 2,600
Ashkenazi Jewish	~13k	1 in 840	none seen
Middle Eastern	~2,884	≈ 1 in 720	≈ 1 in 1,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 8 of 9 coding exons well covered in gnomAD exomes; exon 3 marginal. Genomes: all 9.? see exons ↓