GAD1

Chr 2

glutamate decarboxylase 1

Also known as: CPSQ1, DEE89, GAD, GAD-67, SCP

NCBI Gene: 2571 ENSG00000128683 UniProt: Q99259

This enzyme catalyzes the synthesis of gamma-aminobutyric acid (GABA), the brain's primary inhibitory neurotransmitter, using pyridoxal 5'-phosphate as a cofactor. Autosomal recessive mutations cause developmental and epileptic encephalopathy 89, characterized by pyridoxine-dependent seizures due to deficient GABA production. Loss of enzyme function reduces inhibitory neurotransmission, leading to seizure susceptibility that responds to pyridoxine supplementation.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes one of several forms of glutamic acid decarboxylase, identified as a major autoantigen in insulin-dependent diabetes. The enzyme encoded is responsible for catalyzing the production of gamma-aminobutyric acid from L-glutamic acid. A pathogenic role for this enzyme has been identified in the human pancreas since it has been identified as an autoantigen and an autoreactive T cell target in insulin-dependent diabetes. This gene may also play a role in the stiff man syndrome. Deficiency in this enzyme has been shown to lead to pyridoxine dependency with seizures. Alternative splicing of this gene results in two products, the predominant 67-kD form and a less-frequent 25-kD form. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.47

Clinical Summary— GAD1

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Gene-Disease Validity (ClinGen)

obsolete early infantile epileptic encephalopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.

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ClinVar Variants

18 unique Pathogenic / Likely Pathogenic· 130 VUS of 309 total submissions

Explore recent and relevant literature in Research Assistant →

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?

0.47LOEUF

pLI 0.046

Z-score 3.89

OE 0.27 (0.16–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.32Z-score

OE missense 0.64 (0.58–0.72)

217 obs / 336.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.27 (0.16–0.47)

0≤0.351.4

Missense OE?0.64 (0.58–0.72)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 9 / 33.1Missense obs/exp: 217 / 336.5Syn Z: 0.29

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedGAD1-related cerebral palsy spastic quadriplegicOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6937th %ile

GOF

0.6443th %ile

LOF

0.3744th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

309 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic8

VUS130

Likely Benign108

Benign32

Conflicting14

Pathogenic

Likely Pathogenic

130

VUS

108

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	8	2	0	0	10
Likely Pathogenic	6	2	0	0	8
VUS	1	94	31	4	130
Likely Benign	0	3	46	59	108
Benign	0	1	29	2	32
Conflicting	—				14
Total	15	102	106	65	302

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap GAD1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →