GAD1

Chr 2AR

glutamate decarboxylase 1

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

NCBI Gene: 2571ENSG00000128683UniProt: Q99259

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]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 89MIM #619124
AR
331
ClinVar variants
38
Pathogenic / LP
0.05
pLI score
0
Active trials
Clinical Summary— GAD1
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.
📋
ClinVar Variants
38 Pathogenic / Likely Pathogenic· 132 VUS of 331 total submissions
Some data sources returned errors (1)

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

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.
0.47LOEUF
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?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.
2.32Z-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?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.0.27 (0.16–0.47)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.64 (0.58–0.72)
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.0.97
0≤1.21.6
LoF obs/exp: 9 / 33.1Missense obs/exp: 217 / 336.5Syn Z: 0.29

ClinVar Variant Classifications

331 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30
Likely Pathogenic8
VUS132
Likely Benign108
Benign32
Conflicting14
30
Pathogenic
8
Likely Pathogenic
132
VUS
108
Likely Benign
32
Benign
14
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
1
25
0
30
Likely Pathogenic
2
2
4
0
8
VUS
1
94
33
4
132
Likely Benign
0
3
46
59
108
Benign
0
1
29
2
32
Conflicting
—14
Total710113765324

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

View in ClinVar →

Protein Context — Lollipop Plot

GAD1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

GAD1-related cerebral palsy spastic quadriplegic

limited
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 89

MIM #619124

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression.
Huang D et al.·Nat Cell Biol
2022
A network analysis of depression and anxiety symptoms among Chinese elderly living alone: based on the 2017-2018 Chinese Longitudinal Healthy Longevity Survey (CLHLS).
Chang Z et al.·BMC Psychiatry
2025Natural history
GAD1-mediated GABA elicits aggressive characteristics of human oral cancer cells.
Dou Z et al.·Biochem Biophys Res Commun
2023
GABAergic signaling contributes to tumor cell invasion and poor overall survival in colorectal cancer.
Strelez C et al.·Oncogene
2025
GAD1 ameliorates glioma progression through regulating cuproptosis via RAS/MAPK pathway.
Gao Z et al.·J Biochem Mol Toxicol
2024
Prognostic significance of GAD1 overexpression in patients with resected lung adenocarcinoma.
Tsuboi M et al.·Cancer Med
2019Cohort
Epigenetic control of neurotransmitter expression in olfactory bulb interneurons.
Banerjee K et al.·Int J Dev Neurosci
2013Review
Genetic biomarkers of posttraumatic epilepsy: A systematic review.
Cotter D et al.·Seizure
2017Review
Identification and validation of glucose metabolism-related gene signature in endometrial cancer.
Jiang J et al.·BMC Cancer
2025
Bioinformatics and systems biology approaches to identify the effects of COVID-19 on neurodegenerative diseases: A review.
Bu F et al.·Medicine (Baltimore)
2022Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Therapeutic potential of Cuscutae Semen and Rehmanniae Radix Preparata in age-related central hearing loss associated with Gad1 regulation.
Nam YH et al.·J Ethnopharmacol
2026
GAD1-mediated GABA biosynthesis confers salt tolerance in creeping bentgrass and Arabidopsis thaliana by coordinating osmotic adjustment, ion homeostasis, hormonal signaling, and root system architecture.
Ni W et al.·Plant Physiol Biochem
2025
Abnormally Elevated PKCδ Delays Diabetic Wound Healing by Inhibiting the GAD1-GABA Pathway.
Qin P et al.·Diabetes Metab J
2025
Decoding the role of novel long noncoding RNAs lnc-SLC6A12-1:3 and lnc-SLC6A12-7:5 in regulating the expression of GAD1 and SLC6A12 in cholangiocarcinoma.
Arun SM et al.·Comput Biol Chem
2025
Anlotinib mediates intrinsic drug resistance in hepatoblastoma through the GAD1/GABA pathway.
Huang H et al.·Pediatr Res
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools