Human Gene Module / Chromosome X / GSPT2

GSPT2G1 to S phase transition 2

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
1 / 5
Rare Variants / Common Variants
7 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
Xp11.22
Associated Disorders
-
Relevance to Autism

Wei et al., 2025 described six individuals from six unrelated Chinese families carrying hemizygous missense variants in the GSPT2 gene presenting with severe intellectual disability/learning disability (5/5), developmental delay with severely delayed speech development (5/5), autism spectrum disorder (3/5), ADHD (3/5), seizures (3/5), and brain malformations (3/5); functional assessment of these variants by Western blot analysis of GSPT2-deficient H4 neuroglioma cells transfected with wild-type or mutant HA-GSPT2 demonstrated either reduced or increased protein expression compared to wild-type. Furthermore, Wei et al., 2025 found that GSPT2-deficient H4 cells displayed a slower growth rate and downregulation of cell proliferation and neurodevelopmental markers compared to wild-type cells. A maternally-inherited hemizygous missense variant in GSPT2 was previously identified in a male ASD proband from a simplex family of Middle Eastern ancestry (Gogate et al., 2024), while copy number variation affecting the GSPT2 gene has been previously reported in individuals presenting with syndromic and non-syndromic intellectual disability (Whibley et al., 2010; Grau et al., 2017; Al-Shehhi et al., 2019).

Molecular Function

This gene encodes a GTPase that belongs to the GTP-binding elongation factor family. The encoded protein is a polypeptide release factor that complexes with eukaryotic peptide chain release factor 1 to mediate translation termination. This protein may also be involved in mRNA stability.

External Links
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Human
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SFARI Genomic Platforms
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Reports related to GSPT2 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Fine-scale survey of X chromosome copy number variants and indels underlying intellectual disability Whibley AC , et al. (2010) No -
2 Support - Christina Grau et al. (2017) No -
3 Support - Halima Al-Shehhi et al. (2019) No -
4 Support - Ashlesha Gogate et al. (2024) Yes -
5 Primary - Yuda Wei et al. (2026) No ASD, ADHD, epilepsy/seizures
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.186C>A p.Asn62Lys missense_variant Familial Maternal Simplex 41420448 Wangfang Xie et al. ()
c.449G>T p.Trp150Leu missense_variant Familial Maternal Simplex 41420448 Wangfang Xie et al. ()
c.665A>G p.Gln222Arg missense_variant Familial Maternal Simplex 41420448 Wangfang Xie et al. ()
c.1413A>C p.Glu471Asp missense_variant Familial Maternal Simplex 41420448 Wangfang Xie et al. ()
c.1477A>C p.Ile493Leu missense_variant Familial Maternal Simplex 41420448 Wangfang Xie et al. ()
c.1817T>G p.Phe606Cys missense_variant Familial Maternal Simplex 41420448 Wangfang Xie et al. ()
c.584C>T p.Pro195Leu missense_variant Familial Maternal Simplex 39632905 Ashlesha Gogate et al. (2024)
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 0.48590552333924

Ranking 7277/25841 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 0.90474887017625

Ranking 3197/18225 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 0.93577957279676

Ranking 12985/18665 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 0.4257713895039

Ranking 1169/20870 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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