GABRG2

Chr 5

gamma-aminobutyric acid type A receptor subunit gamma2

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

NCBI Gene: 2566ENSG00000113327UniProt: P18507

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]

Primary Disease Associations & Inheritance

UniProtDevelopmental and epileptic encephalopathy 74
UniProtEpilepsy, childhood absence 2
UniProtFebrile seizures, familial, 8
UniProtGeneralized epilepsy with febrile seizures plus 3
521
ClinVar variants
111
Pathogenic / LP
0.74
pLI score
1
Active trials
Clinical Summary— GABRG2
🧬
Gene-Disease Validity (ClinGen)
epilepsy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.74) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
111 Pathogenic / Likely Pathogenic· 219 VUS of 521 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.19 (0.10–0.40)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.49 (0.43–0.57)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.10
0≤1.21.6
LoF obs/exp: 5 / 26.4Missense obs/exp: 137 / 277.3Syn Z: -0.79

ClinVar Variant Classifications

521 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic60
Likely Pathogenic51
VUS219
Likely Benign151
Benign20
Conflicting20
60
Pathogenic
51
Likely Pathogenic
219
VUS
151
Likely Benign
20
Benign
20
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
18
12
30
0
60
Likely Pathogenic
15
19
17
0
51
VUS
7
178
29
5
219
Likely Benign
0
5
65
81
151
Benign
0
5
11
4
20
Conflicting
—20
Total4021915290521

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

View in ClinVar →

Protein Context — Lollipop Plot

GABRG2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

GABRG2-related epilepsy, generalized, with febrile seizures plus

strong
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — GABRG2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.
Wang T et al.·Nat Commun
2020
Genetic variations in GABA metabolism and epilepsy.
Feng Y et al.·Seizure
2022Review
Molecular and clinical descriptions of patients with GABA(A) receptor gene variants (GABRA1, GABRB2, GABRB3, GABRG2): A cohort study, review of literature, and genotype-phenotype correlation.
Maillard PY et al.·Epilepsia
2022Review
Understanding paralogous epilepsy-associated GABA(A) receptor variants: Clinical implications, mechanisms, and potential pitfalls.
Kan ASH et al.·Proc Natl Acad Sci U S A
2024Functional
Pathogenic role of acyl coenzyme A binding protein (ACBP) in Cushing's syndrome.
Pan H et al.·Nat Metab
2024
Phenotypic Spectrum in Individuals With Pathogenic GABRG2 Loss- and Gain-of-Function Variants.
Rossi A et al.·Neurology
2025
Investigating the effect of polygenic background on epilepsy phenotype in 'monogenic' families.
Oliver KL et al.·EBioMedicine
2024
GABRG2 Variants Associated with Febrile Seizures.
Hernandez CC et al.·Biomolecules
2023
Molecular Pathogenic Basis for GABRG2 Mutations Associated With a Spectrum of Epilepsy Syndromes, From Generalized Absence Epilepsy to Dravet Syndrome.
Kang JQ et al.·JAMA Neurol
2016Review
Genetic Causes of Generalized Epilepsies.
Helbig I·Semin Neurol
2015Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Increased excitability of layer 5 neocortical pyramidal neurons and its contribution to seizure activity in Gabrg2 gene-deficient mice.
Sun Y et al.·iScience
2026🔓 Open Access
Early neurological symptoms and epilepsy outcomes in individuals with the recurrent GABRG2 p.(Ala106Thr) gain-of-function variant: Structural and phenotypic insights.
Ortiz S et al.·Epilepsia
2025
Beyond Impaired GABAergic Signaling: Inflammation and Metabolic Dysfunction in Genetic Epilepsy Induced by GABRG2 Mutation.
Shen D et al.·Mol Neurobiol
2025
Association of GABRG2 gene polymorphisms with idiopathic generalized epilepsy in Egyptian children: a case-control study.
Wahba Y et al.·Eur J Med Res
2025🔓 Open Access
A knock-in mouse model for GABRG2-related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment.
Shen D et al.·Cell Death Discov
2025🔓 Open AccessFunctional
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Epilepsy

Precision Medicine in the Treatment of Epilepsy

RECRUITING
NCT05450822Gitte Moos KnudsenStarted 2022-02-18
LevetiracetamLevetiracetam TabletsLamotrigine tablet

External Resources

Links to major genomics databases and tools