Human Gene Module / Chromosome 2 / GLS

GLSglutaminase

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
2 / 6
Rare Variants / Common Variants
4 / 0
Aliases
-
Associated Syndromes
CASGID syndrome
Chromosome Band
2q32.2
Associated Disorders
-
Relevance to Autism

TADA analysis of >15,000 Latin American individuals from the GALA Consortium (including 4,717 participants with an ASD diagnosis) in Avila et al., 2026 identified GLS as one of 35 genes reaching genome-wide significance (FDR < 0.05); the two Admixed American (AMR) individuals with ASD included in this analysis were SPARK probands originally reported in Zhou et al., 2022 with de novo missense variants with MPC scores > 2. Zhou et al., 2022 also reported two additional de novo GLS variants in SPARK probands that were not included in the Avila et al., 2026 TADA analysis (one loss-of-function variant, one missense variant).

Molecular Function

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. Heterozygous gain-of-function mutations in GLS are thought to be responsible for CASGID syndrome (Rumping et al., 2019; Rumping et al., 2023), whereas biallelic variants in this gene are thought to cause either developmental and epileptic encephalopathy 71 (Rumping et al., 2019) or global developmental delay, progressive ataxia, and elevated glutamine (van Kuilenburg et al., 2019).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to GLS (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Rumping, Lynne et al. (2019) No -
2 Support - Rumping, Lynne et al. (2019) No -
3 Support - van Kuilenburg, Andre B P et al. (2019) No -
4 Support - Zhou X et al. (2022) Yes -
5 Support - Rumping, Lynne et al. (2023) No -
6 Primary - Natividad Avila, Marina et al. (2026) Yes -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1248+1G>A p.? splice_site_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1786G>C p.Glu596Gln missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1395G>A p.Met465Ile missense_variant De novo - Unknown 35982159 Zhou X et al. (2022)
c.1637G>A p.Gly546Asp missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2026
3

Initial score established: 3

Krishnan Probability Score

Score 0.50587562393876

Ranking 1895/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99930259969698

Ranking 999/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.74613148743356

Ranking 1517/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.41996452382277

Ranking 1234/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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