GLUL

Chr 1ADAR

glutamate-ammonia ligase

Also known as: DEE116, GLNS, GS, PIG43, PIG59

NCBI Gene: 2752 ENSG00000135821 UniProt: P15104 OMIM: 138290

The protein catalyzes the ATP-dependent synthesis of glutamine from glutamate and ammonia, serving critical functions in ammonia detoxification, acid-base homeostasis, and providing glutamine for amino acid, pyrimidine, and purine biosynthesis. Loss-of-function mutations cause congenital glutamine deficiency and developmental and epileptic encephalopathy 116 through both autosomal dominant and autosomal recessive inheritance patterns. The high pLI score (0.996) indicates this gene is highly intolerant to loss-of-function variants, consistent with its essential metabolic role.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene belongs to the glutamine synthetase family. It catalyzes the synthesis of glutamine from glutamate and ammonia in an ATP-dependent reaction. This protein plays a role in ammonia and glutamate detoxification, acid-base homeostasis, cell signaling, and cell proliferation. Glutamine is an abundant amino acid, and is important to the biosynthesis of several amino acids, pyrimidines, and purines. Mutations in this gene are associated with congenital glutamine deficiency, and overexpression of this gene was observed in some primary liver cancer samples. There are six pseudogenes of this gene found on chromosomes 2, 5, 9, 11, and 12. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.182 OMIM phenotypes

Clinical Summary— GLUL

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Gene-Disease Validity (ClinGen)

congenital brain dysgenesis due to glutamine synthetase deficiency · ARModerate

Moderate evidence — consider for supplementary testing

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 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

13 unique Pathogenic / Likely Pathogenic· 153 VUS of 284 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.18LOEUF

pLI 0.996

Z-score 3.72

OE 0.00 (0.00–0.18)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.60Z-score

OE missense 0.70 (0.61–0.80)

156 obs / 223.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.18)

0≤0.351.4

Missense OE?0.70 (0.61–0.80)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 0 / 16.1Missense obs/exp: 156 / 223.5Syn Z: -1.39

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGLUL-related congenital systemic glutamine deficiencyOTHERAR

This gene — mechanism propensity

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

0.3793th %ile

GOF

0.3590th %ile

LOF

0.66top 25%

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

284 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic8

VUS153

Likely Benign67

Benign32

Conflicting6

Pathogenic

Likely Pathogenic

153

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	4	0	0	5
Likely Pathogenic	2	6	0	0	8
VUS	7	76	69	1	153
Likely Benign	0	1	35	31	67
Benign	0	0	29	3	32
Conflicting	—				6
Total	10	87	133	35	271

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

View in ClinVar →

29 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap GLUL — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →