GABRG3

Chr 15

gamma-aminobutyric acid type A receptor subunit gamma3

The GABRG3 protein is a gamma subunit of GABA-A receptors, pentameric ligand-gated chloride channels that mediate inhibitory neurotransmission in the brain and contain the benzodiazepine binding site. Mutations cause autosomal recessive epileptic encephalopathy with intellectual disability and developmental delays. This gene is highly constrained against loss-of-function variants (pLI 0.85, LOEUF 0.39), indicating that such mutations are likely to have significant clinical consequences.

ResearchSummary from RefSeq, UniProt

Gamma subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain (By similarity). 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 across the cell membrane down their electrochemical gradient (By similarity)

ResearchGenerating clinical summary…

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

0.39

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (2)

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

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.39LOEUF

pLI 0.847

Z-score 3.76

OE 0.17 (0.08–0.39)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.52Z-score

OE missense 0.56 (0.49–0.64)

145 obs / 259.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.17 (0.08–0.39)

0≤0.351.4

Missense OE?0.56 (0.49–0.64)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 4 / 23.8Missense obs/exp: 145 / 259.1Syn Z: -0.17

Background carrier burden — how many people carry a rare variant somewhere in GABRG3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 83

529 rare PASS variants

Rare truncating (LoF)

1 in 1,200

78 rare PASS variants

Rare synonymous (reference)

1 in 150

276 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GABRG3. 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 180	1 in 1,100
South Asian	~43k	1 in 70	1 in 3,000
Remaining (unassigned)	~30k	1 in 78	1 in 4,300
European (Finnish)	~27k	1 in 410	≈ 1 in 6,800
Admixed American	~22k	1 in 110	1 in 1,700
African / African American	~21k	1 in 100	1 in 420
East Asian	~20k	1 in 110	1 in 2,100
Ashkenazi Jewish	~13k	≈ 1 in 3,000	1 in 460
Middle Eastern	~2,884	1 in 89	≈ 1 in 1,400

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 10 coding exons well covered in gnomAD exomes; exons 3, 9 marginal. Genomes: all 10.? see exons ↓