GABRA5

Chr 15

gamma-aminobutyric acid type A receptor subunit alpha5

Also known as: DEE79, EIEE79

NCBI Gene: 2558 ENSG00000186297 UniProt: P31644

The protein encoded by this gene forms part of GABA-A receptors, which are ligand-gated chloride channels that mediate the major inhibitory neurotransmission in the brain. Mutations cause developmental and epileptic encephalopathy 79 through an autosomal dominant inheritance pattern via a gain-of-function mechanism. The gene is highly constrained against loss-of-function variants, consistent with the pathogenic mechanism being gain-of-function rather than haploinsufficiency.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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. Transcript variants utilizing three different alternative non-coding first exons have been described. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtDevelopmental and epileptic encephalopathy 79

Clinical highlights

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

0.37

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.37LOEUF

pLI 0.905

Z-score 3.62

OE 0.14 (0.07–0.37)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.23Z-score

OE missense 0.46 (0.39–0.53)

127 obs / 278.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.14 (0.07–0.37)

0≤0.351.4

Missense OE?0.46 (0.39–0.53)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 3 / 20.8Missense obs/exp: 127 / 278.8Syn Z: -0.25

Background carrier burden — how many people carry a rare variant somewhere in GABRA5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 180

394 rare PASS variants

Rare truncating (LoF)

1 in 7,300

41 rare PASS variants

Rare synonymous (reference)

1 in 160

251 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GABRA5. 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 250	1 in 6,800
South Asian	~43k	1 in 320	none seen
Remaining (unassigned)	~30k	1 in 230	none seen
European (Finnish)	~27k	1 in 410	1 in 3,800
Admixed American	~22k	1 in 320	≈ 1 in 11,000
African / African American	~21k	1 in 270	none seen
East Asian	~20k	1 in 360	1 in 2,500
Ashkenazi Jewish	~13k	1 in 770	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 220	none seen

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.