GLS

Chr 2ADAR

glutaminase

ENSG00000115419 UniProt: O94925 OMIM: 138280

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine. Plays a role in maintaining acid-base homeostasis. Regulates the levels of the neurotransmitter glutamate, the main excitatory neurotransmitter in the brain (PubMed:30239721, PubMed:30575854, PubMed:30970188)

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.323 OMIM phenotypes

Clinical Summary— GLS

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Gene-Disease Validity (ClinGen)

glutaminase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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.

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ClinVar Variants

19 unique Pathogenic / Likely Pathogenic· 92 VUS of 176 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.16 (0.09–0.32)

0≤0.351.4

Missense OE?0.41 (0.36–0.48)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 6 / 36.6Missense obs/exp: 133 / 321.1Syn Z: 0.92

This gene — mechanism propensity

0.3892th %ile

GOF

0.5169th %ile

LOF

0.67top 25%

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.

LOFprediction above median · 53% of P/LP variants are LoF · LOEUF 0.32

GOF1 literature citation

Literature Evidence

GOFWe extend these findings to AML subtypes driven by other tyrosine kinase (TK) activating mutations and validate the role of GLS as a clinically actionable therapeutic target in both primary AML and in vivo models.1

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

References

1.PMID 29463564 ↗

ClinVar Variant Classifications

176 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic8

VUS92

Likely Benign34

Benign5

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	4	1	0	11
Likely Pathogenic	4	4	0	0	8
VUS	1	88	3	0	92
Likely Benign	0	5	17	12	34
Benign	0	2	2	1	5
Conflicting	—				1
Total	11	103	23	13	151

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

View in ClinVar →

29 pathogenic / likely-pathogenic (of 33) ClinVar copy-number / structural variants overlap GLS — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

GLS · protein map & ClinVar variants

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

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Dilated Cardiomyopathy

Observational Study of Natural History of BAG3 Gene Mutation-Associated Dilated Cardiomyopathy in Chinese Adults

NOT YET RECRUITING

NCT07646600AstraZenecaStarted 2026-06-29

Observational, None intervention

Stage III Colon Cancer

Colon Adjuvant Chemotherapy Based on Evaluation of Residual Disease

RECRUITING

NCT05174169Phase PHASE2, PHASE3NRG OncologyStarted 2022-07-08

Signatera testmFOLFOX6 3-6 monthCAPOX 3 month

Metastatic Renal Cell CarcinomaSarcomatoid Renal Cell CarcinomaStage II Renal Cell Cancer AJCC v7

Nivolumab in Treating Patients With Localized Kidney Cancer Undergoing Nephrectomy

ACTIVE NOT RECRUITING

NCT03055013Phase PHASE3National Cancer Institute (NCI)Started 2017-04-28

NephrectomyNivolumabPatient Observation

Heart Failure With Reduced Ejection Fraction (HFrEF)Chronic Heart Failure

Vericiguat and Reverse Remodeling Indices in Heart Failure

RECRUITING

NCT07405944Phase PHASE4University Medical Centre LjubljanaStarted 2025-11-01

VericiguatGuideline Directed Medical Therapy for Heart Failure (GDMT)

Human Gut Microbiota

The QIB Colon Model

ENROLLING BY INVITATION

NCT02653001Phase NAQuadram Institute BioscienceStarted 2015-12-18

Stool sample collection

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

Recurrent Non-Small Cell Lung CarcinomaStage IV Non-Small Cell Lung Cancer

Maintenance Chemotherapy With or Without Local Consolidative Therapy in Treating Patients With Stage IV Non-small Cell Lung Cancer

ACTIVE NOT RECRUITING

NCT03137771Phase PHASE2NRG OncologyStarted 2017-04-07

3-Dimensional Conformal Radiation Therapy (3D-CRT)DocetaxelGemcitabine

Anatomic Stage IV Breast Cancer AJCC v8Invasive Breast CarcinomaMetastatic Triple-Negative Breast Carcinoma

Testing the Addition of an Individualized Vaccine to Durvalumab and Tremelimumab and Chemotherapy in Patients With Metastatic Triple Negative Breast Cancer

RECRUITING

NCT03606967Phase PHASE2National Cancer Institute (NCI)Started 2021-04-13

Biopsy ProcedureBiospecimen CollectionCarboplatin

Prostate Cancer

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

ACTIVE NOT RECRUITING

NCT01368588Phase PHASE3Radiation Therapy Oncology GroupStarted 2011-07

three-dimensional conformal radiotherapyintensity modulated radiotherapyBrachytherapy

Breast CancerCognitive Impairments

Cognitive Training for Cancer Related Cognitive Impairment in Breast Cancer Survivors

RECRUITING

NCT05896189Phase NANRG OncologyStarted 2024-02-29