GABRG2

Chr 5AD

gamma-aminobutyric acid type A receptor subunit gamma2

Also known as: CAE2, DEE74, ECA2, EIEE74, FEB8, GEFSP3

NCBI Gene: 2566 ENSG00000113327 UniProt: P18507 OMIM: 137164

The gene encodes the gamma-2 subunit of GABA-A receptors, which are pentameric ligand-gated chloride channels that mediate inhibitory neurotransmission in the brain. Mutations cause autosomal dominant epilepsy syndromes including developmental and epileptic encephalopathy, generalized epilepsy with febrile seizures plus, and familial febrile seizures. Disease can result from multiple mechanisms depending on the specific variant, with some mutations causing loss of receptor function while others may produce dominant-negative or gain-of-function 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 mammlian brain, where it acts at GABA-A receptors, which are ligand-gated chloride channels. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene have been associated with epilepsy and febrile seizures. Multiple transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOF/DNmechanismADLOEUF 0.403 OMIM phenotypes

Clinical Summary— GABRG2

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Gene-Disease Validity (ClinGen)

epilepsy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.74) — some intolerance to loss-of-function variants.

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ClinVar Variants

149 unique Pathogenic / Likely Pathogenic· 336 VUS of 791 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 →

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GeneReview available — GABRG2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.40LOEUF

pLI 0.739

Z-score 3.86

OE 0.19 (0.10–0.40)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.99Z-score

OE missense 0.49 (0.43–0.57)

137 obs / 277.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.19 (0.10–0.40)

0≤0.351.4

Missense OE?0.49 (0.43–0.57)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 5 / 26.4Missense obs/exp: 137 / 277.3Syn Z: -0.79

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongGABRG2-related epilepsy, generalized, with febrile seizures plusLOFAD

Mechanism Note (variant-dependent)

LOFDN— mechanism depends on specific variant

GABA-A receptor gamma-2 subunit forms pentameric channels. Most pathogenic truncating mutations produce stable mutant proteins with dominant-negative effects on channel assembly. Missense variants reduce surface expression or channel function (LOF). Both LOF and DN mechanisms are established; GOF is not the primary mechanism despite Badonyi prediction.12

This gene — mechanism propensity

0.7131th %ile

GOF

0.73top 25%

LOF

0.4233th %ile

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

DNprediction above median · 1 literature citation

GOFprediction above median

LOF52% of P/LP variants are LoF · LOEUF 0.40

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

DNMost GABRG2 truncating mutations associated with Dravet syndrome result in premature termination codons (PTCs) and are stably translated into mutant proteins with potential dominant-negative effects.1

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

791 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic81

Likely Pathogenic68

VUS336

Likely Benign209

Benign35

Conflicting57

Pathogenic

Likely Pathogenic

336

VUS

209

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	47	14	20	0	81
Likely Pathogenic	31	31	6	0	68
VUS	13	252	65	6	336
Likely Benign	0	12	88	109	209
Benign	0	5	25	5	35
Conflicting	—				57
Total	91	314	204	120	786

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

View in ClinVar →

25 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap GABRG2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →