GABRA3

Chr XX-linked

gamma-aminobutyric acid type A receptor subunit alpha3

ENSG00000011677 UniProt: P34903 OMIM: 305660

The protein functions as an alpha subunit of GABA-A receptors, heteropentameric ligand-gated chloride channels that mediate inhibitory neurotransmission in the brain by allowing chloride influx when activated by GABA. Mutations cause X-linked epilepsy with or without intellectual disability and dysmorphic features, following X-linked inheritance. The gene shows relatively low constraint to loss-of-function variation (pLI 0.04, LOEUF 0.70).

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain (PubMed:16412217, PubMed:29053855). GABA-gated chloride channels, also named GABA(A) receptors (GABAAR), consist of five subunits arranged around a central pore and contain GABA active binding site(s) located at the alpha and beta subunit interface(s) (By similarity). When activated by GABA, GABAARs selectively allow the flow of chloride anions across the cell membrane down their electrochemical gradient (PubMed:16412217, PubMed:29053855). Chloride influx into the postsynaptic neuron following GABAAR opening decreases the neuron ability to generate a new action potential, thereby reducing nerve transmission (PubMed:16412217, PubMed:29053855)

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic featuresMIM #301091

X-linked

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features; no ClinGen or GenCC tier

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.70

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.70LOEUF

pLI 0.039

Z-score 2.40

OE 0.33 (0.17–0.70)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.53Z-score

OE missense 0.49 (0.42–0.58)

97 obs / 196.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.33 (0.17–0.70)

0≤0.351.4

Missense OE?0.49 (0.42–0.58)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 5 / 15.0Missense obs/exp: 97 / 196.8Syn Z: 0.68

Background carrier burden — how many people carry a rare variant somewhere in GABRA3?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 570

249 rare PASS variants

Rare truncating (LoF)

1 in 20,000

19 rare PASS variants

Rare synonymous (reference)

1 in 300

167 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GABRA3. 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)	~561k	1 in 680	1 in 24,000
South Asian	~36k	1 in 360	none seen
Remaining (unassigned)	~31k	1 in 580	≈ 1 in 31,000
European (Finnish)	~27k	1 in 3,400	none seen
Admixed American	~23k	1 in 490	none seen
African / African American	~21k	1 in 360	≈ 1 in 20,000
East Asian	~20k	1 in 420	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 1,800	none seen
Middle Eastern	~2,758	1 in 450	≈ 1 in 2,800

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): All 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓