Human Gene Module / Chromosome 12 / KSR2

KSR2kinase suppressor of ras 2

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
5 / 5
Rare Variants / Common Variants
7 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
12q24.22-q24.23
Associated Disorders
-
Relevance to Autism

Whole-exome sequencing of 115 ASD trios from three countries with a high frequency of consanguineous populations (Pakistan, Iran, and Saudi Arabia) in Harripaul et al., 2026 identified a homozygous missense variant in the KSR2 gene (NM_173598.6:c.763C>T;p.Arg255Trp) in a male ASD proband from Iran. De novo variants in this gene, including a de novo loss-of-function variant, have been reported in ASD probands from the SPARK cohort and a Chinese ASD cohort (Zhou et al., 2022; Trost et al., 2022; Wang et al., 2023; Avila et al., 2026).

Molecular Function

Enables protein serine/threonine kinase activity. Predicted to be involved in Ras protein signal transduction; calcium-mediated signaling; and positive regulation of cold-induced thermogenesis. Predicted to act upstream of or within positive regulation of MAPK cascade. Predicted to be located in membrane. Predicted to be active in cytosol and plasma membrane.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KSR2 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Zhou X et al. (2022) Yes -
2 Support - Trost B et al. (2022) Yes -
3 Support - Wang J et al. (2023) Yes -
4 Primary - Harripaul, Ricardo et al. (2026) Yes -
5 Support - Natividad Avila, Marina et al. (2026) Yes -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.403G>A p.Gly135Arg missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.1463G>A p.Arg488His missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1600C>A p.Pro534Thr missense_variant De novo - Simplex 36368308 Trost B et al. (2022)
c.1755G>A p.Pro585= synonymous_variant De novo - Simplex 36368308 Trost B et al. (2022)
c.1600_1601delinsA p.Pro534ThrfsTer63 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2108C>T p.Pro703Leu missense_variant De novo - Multiplex 41912808 Natividad Avila, Marina et al. (2026)
c.763C>T p.Arg255Trp missense_variant Familial Both parents Simplex 41865132 Harripaul, Ricardo et al. (2026)
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 0.48850321457346

Ranking 6726/25841 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 0.99994662468572

Ranking 597/18225 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 0.94283839752633

Ranking 15458/18665 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
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