GLS

Chr 2ADAR

glutaminase

Also known as: AAD20, CASGID, DEE71, EIEE71, GAC, GAM, GDPAG, GLS1

NCBI Gene: 2744ENSG00000115419UniProt: O94925

This gene encodes the K-type mitochondrial glutaminase. The encoded protein is an phosphate-activated amidohydrolase that catalyzes the hydrolysis of glutamine to glutamate and ammonia. This protein is primarily expressed in the brain and kidney plays an essential role in generating energy for metabolism, synthesizing the brain neurotransmitter glutamate and maintaining acid-base balance in the kidney. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]

Primary Disease Associations & Inheritance

CASGID syndromeMIM #618339
AD
Developmental and epileptic encephalopathy 71MIM #618328
AR
Global developmental delay, progressive ataxia, and elevated glutamineMIM #618412
AR
179
ClinVar variants
47
Pathogenic / LP
0.96
pLI score· haploinsufficient
12
Active trials
Clinical Summary— GLS
🧬
Gene-Disease Validity (ClinGen)
glutaminase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
47 Pathogenic / Likely Pathogenic· 93 VUS of 179 total submissions
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.32LOEUF
pLI 0.962
Z-score 4.69
OE 0.16 (0.09–0.32)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
3.73Z-score
OE missense 0.41 (0.36–0.48)
133 obs / 321.1 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.16 (0.09–0.32)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.41 (0.36–0.48)
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.0.89
0≤1.21.6
LoF obs/exp: 6 / 36.6Missense obs/exp: 133 / 321.1Syn Z: 0.92

ClinVar Variant Classifications

179 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38
Likely Pathogenic9
VUS93
Likely Benign33
Benign5
Conflicting1
38
Pathogenic
9
Likely Pathogenic
93
VUS
33
Likely Benign
5
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
4
31
0
38
Likely Pathogenic
3
4
2
0
9
VUS
1
83
9
0
93
Likely Benign
0
4
17
12
33
Benign
0
2
2
1
5
Conflicting
—1
Total7976113179

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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
GLUTAMINASE; GLS
MIM #138280 · *

CASGID syndrome

MIM #618339

Molecular basis of disorder known

Autosomal dominant

Developmental and epileptic encephalopathy 71

MIM #618328

Molecular basis of disorder known

Autosomal recessive

Global developmental delay, progressive ataxia, and elevated glutamine

MIM #618412

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — GLS
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
[The Japanese Clinical Guidelines 2022 for Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome: An Overview].
Murai H·Brain Nerve
2024Review
Assessment of Left Ventricular Function by Echocardiography: The Case for Routinely Adding Global Longitudinal Strain to Ejection Fraction.
Potter E et al.·JACC Cardiovasc Imaging
2018Review
Myocardial Strain Measured by Cardiac Magnetic Resonance Predicts Cardiovascular Morbidity and Death.
Chadalavada S et al.·J Am Coll Cardiol
2024
Inhibition of Glutamate-to-Glutathione Flux Promotes Tumor Antigen Presentation in Colorectal Cancer Cells.
Yu T et al.·Adv Sci (Weinh)
2025
Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis-Study of Treatment's Echocardiographic Mechanisms (CLOVERS-STEM).
Lanspa MJ et al.·Crit Care Explor
2024Functional
Effect of Empagliflozin and Pioglitazone on left ventricular function in patients with type two diabetes and nonalcoholic fatty liver disease without established cardiovascular disease: a randomized single-blind clinical trial.
Attaran F et al.·BMC Gastroenterol
2023Cohort
Clinical and echocardiographic phenotype of cardiac wasting in patients with advanced cancer.
Anker MS et al.·Eur J Heart Fail
2025Cohort
The suppressive role of GLS in radiosensitivity and irradiation-induced immune response in LUAD: integrating bioinformatics and experimental insights.
Jiang P et al.·Front Immunol
2025
Associations between cuprotosis-related genes and the spectrum of metabolic dysfunction-associated fatty liver disease: An exploratory study.
Yuan HY et al.·Diabetes Obes Metab
2024
Gastroparesis Updates on Pathogenesis and Management.
Liu N et al.·Gut Liver
2017Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
DNA methylation-driven gene-based drug response prediction model for liver cancer: The critical role of GLS.
Zheng S et al.·PLoS One
2025🔓 Open AccessFunctional
Clinical Usefulness of Left Ventricular Global Longitudinal Strain as a Predictor of Prognosis in Patients With Acute Ischemic Stroke (GLS-STROKE Study).
Kim M et al.·J Am Heart Assoc
2025🔓 Open AccessCohort
The effects of interfering with gs and gls genes on intestinal genes expression and metabolic pathways in Trachinotus blochii.
Chen C et al.·Comp Biochem Physiol Part D Genomics Proteomics
2026
Ouabain-mediated IGF2BP2-GLS/NOS3 axis affects arginine metabolism in diffuse large B-cell lymphoma.
Hong Y et al.·Eur J Med Res
2025🔓 Open Access
The potential impact of GLS and PDHA1 on tumor immunity and immunotherapy response in LUSC.
Ling T et al.·Front Genet
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Advanced Malignant Solid NeoplasmMetastatic Malignant Solid NeoplasmNF1 Mutation Positive Malignant Peripheral Nerve Sheath Tumor

Testing Whether Cancers With Specific Mutations Respond Better to Glutaminase Inhibitor, Telaglenastat Hydrochloride, Anti-Cancer Treatment, BeGIN Study

ACTIVE NOT RECRUITING
NCT03872427Phase PHASE2National Cancer Institute (NCI)Started 2019-12-14
Biospecimen CollectionComputed TomographyMagnetic Resonance Imaging
AutismAutistic DisorderAutism Spectrum Disorder

Sulforaphane in a New Jersey (NJ) Population of Individuals With Autism

ACTIVE NOT RECRUITING
NCT02677051Phase PHASE2Rutgers, The State University of New JerseyStarted 2016-02
SulforaphanePlacebo
Brain Injuries

The Gut-Brain Axis During Neurorehabilitation; Prebiotic Treatment to Alter the Gut Microbiome and Neurologic Symptoms

RECRUITING
NCT06607523Phase NAThe University of Texas Medical Branch, GalvestonStarted 2025-03-06
Inulin
Advanced Malignant Solid NeoplasmMetastatic Malignant Solid NeoplasmUnresectable Malignant Solid Neoplasm

Testing the Combination of the Anti-cancer Drugs ZEN003694 (ZEN-3694) and Talazoparib in Patients With Advanced Solid Tumors, The ComBET Trial

RECRUITING
NCT05327010Phase PHASE2National Cancer Institute (NCI)Started 2022-11-14
BET Bromodomain Inhibitor ZEN-3694Biopsy ProcedureBiospecimen Collection
Advanced Bladder CarcinomaAdvanced Genitourinary System CarcinomaMetastatic Bladder Carcinoma

Testing Olaparib in Patients With Advanced or Metastatic (Cancer That Has Spread) Bladder Cancer and Other Genitourinary Tumors With DNA-Repair Genetic Changes

RECRUITING
NCT03375307Phase PHASE2National Cancer Institute (NCI)Started 2020-11-03
Biopsy ProcedureBiospecimen CollectionBone Marrow Biopsy
Stage II Breast CancerStage IIIA Breast Cancer

Comparison of Axillary Lymph Node Dissection with Axillary Radiation for Patients with Node-Positive Breast Cancer Treated with Chemotherapy

ACTIVE NOT RECRUITING
NCT01901094Phase PHASE3Alliance for Clinical Trials in OncologyStarted 2014-02-24
Axillary Lymph Node Dissection (ALND)Nodal Radiation TherapyAxillary Radiation Therapy
Prostate Cancer

Androgen-Deprivation Therapy and Radiation Therapy in Treating Patients With Prostate Cancer

ACTIVE NOT RECRUITING
NCT01368588Phase PHASE3Radiation Therapy Oncology GroupStarted 2011-07
radiation therapyWhole-pelvic radiotherapy (WPRT)
Breast Cancer

Evaluating 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

RECRUITING
NCT05879926Phase PHASE3NRG OncologyStarted 2023-08-31
Ovarian Function Suppression + Aromatase InhibitorAdjuvant Chemotherapy + Ovarian Function Suppression
GanglioneuroblastomaLocalized Resectable NeuroblastomaLocalized Unresectable Neuroblastoma

Biomarkers in Tumor Tissue Samples From Patients With Newly Diagnosed Neuroblastoma or Ganglioneuroblastoma

ACTIVE NOT RECRUITING
NCT00904241Children's Oncology GroupStarted 2000-11-06
Cytology Specimen Collection ProcedureLaboratory Biomarker Analysis
Breast CancerCognitive Impairments

Cognitive Training for Cancer Related Cognitive Impairment in Breast Cancer Survivors

RECRUITING
NCT05896189Phase NANRG OncologyStarted 2024-04-12
Arm 1: Computerized Cognitive Training-Global Stimulation GamesArm 2: Computerized Cognitive Training-Neuroplasticity Games
Advanced Lung Non-Small Cell CarcinomaMetastatic Lung Non-Small Cell CarcinomaStage IV Lung Cancer AJCC v8

Telaglenastat Hydrochloride and Osimertinib in Treating Patients With EGFR-Mutated Stage IV Non-small Cell Lung Cancer

ACTIVE NOT RECRUITING
NCT03831932Phase PHASE1, PHASE2National Cancer Institute (NCI)Started 2020-03-16
Biospecimen CollectionComputed TomographyMagnetic Resonance Elastography
Stage I Breast Cancer

De-Escalation of Breast Radiation Trial for Hormone Sensitive, HER-2 Negative, Oncotype Recurrence Score Less Than or Equal to 18 Breast Cancer (DEBRA)

RECRUITING
NCT04852887Phase PHASE3NRG OncologyStarted 2021-06-07
Radiation and Endocrine Therapy (Tamoxifen, Anastrozol, Letrozole, Exemestane)Endocrine Therapy (Tamoxifen, Anastrozol, Letrozole, Exemestane)

External Resources

Links to major genomics databases and tools