GLS
Chr 2ADARglutaminase
Also known as: AAD20, CASGID, DEE71, EIEE71, GAC, GAM, GDPAG, GLS1
The encoded mitochondrial glutaminase catalyzes the hydrolysis of glutamine to glutamate and ammonia, serving essential roles in energy metabolism, glutamate neurotransmitter synthesis in the brain, and acid-base balance in the kidney. Loss-of-function mutations cause CASGID syndrome, developmental and epileptic encephalopathy 71, and global developmental delay with progressive ataxia and elevated glutamine through both autosomal dominant and autosomal recessive inheritance patterns. The high pLI score (0.96) indicates this gene is highly intolerant to loss-of-function variants, consistent with its essential metabolic functions.
Definitive — sufficient evidence for diagnostic panels
2 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Highly missense-constrained (top ~0.1%)
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Literature Evidence
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
108 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 4 | 3 | 28 | 0 | 35 |
Likely Pathogenic | 2 | 3 | 1 | 0 | 6 |
VUS | 0 | 37 | 4 | 0 | 41 |
Likely Benign | 0 | 3 | 12 | 5 | 20 |
Benign | 0 | 2 | 2 | 1 | 5 |
Conflicting | — | 1 | |||
| Total | 6 | 48 | 47 | 6 | 108 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
GLS · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Treating Breast Cancer Patients Undergoing Trastuzumab Treatment With Carvedilol to Reduce Incidence of Heart Failure
ACTIVE NOT RECRUITINGVericiguat and Reverse Remodeling Indices in Heart Failure
RECRUITINGBroccoli Effect on Glycated Haemoglobin (HbA1c)
ACTIVE NOT RECRUITINGComparison of Axillary Lymph Node Dissection with Axillary Radiation for Patients with Node-Positive Breast Cancer Treated with Chemotherapy
ACTIVE NOT RECRUITINGMyrosinase Bioactivated Gglucoraphanin for the Treatment of Neurodegenerative Diseases (GRA-MYR-ND)
RECRUITINGEXpanding Prenatal Cell Free DNA Screening Across moNogenic Disorders (EXPAND)
RECRUITINGTesting the Addition of an Individualized Vaccine to Durvalumab and Tremelimumab and Chemotherapy in Patients With Metastatic Triple Negative Breast Cancer
RECRUITINGMaintenance Chemotherapy With or Without Local Consolidative Therapy in Treating Patients With Stage IV Non-small Cell Lung Cancer
ACTIVE NOT RECRUITINGTesting Whether Cancers With Specific Mutations Respond Better to Glutaminase Inhibitor, Telaglenastat Hydrochloride, Anti-Cancer Treatment, BeGIN Study
ACTIVE NOT RECRUITINGEvaluating the Addition of Adjuvant Chemotherapy to Ovarian Function Suppression Plus Endocrine Therapy in Premenopausal Patients With pN0-1, ER-Positive/HER2-Negative Breast Cancer and an Oncotype Recurrence Score Less Than or Equal to 25
RECRUITINGAcute Porphyria Biomarkers for Disease Activity
ACTIVE NOT RECRUITINGNatural History in Fabry Disease With IVS4+919G>A Mutations
ACTIVE NOT RECRUITINGExternal Resources
Links to major genomics databases and tools