Human Gene Module / Chromosome 5 / PPP2CA

PPP2CAprotein phosphatase 2 catalytic subunit alpha

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
3 / 5
Rare Variants / Common Variants
21 / 0
Aliases
PPP2CA, PP2Ac,  PP2CA,  PP2Calpha,  RP-C
Associated Syndromes
-
Chromosome Band
5q31.1
Associated Disorders
ASD, EPS
Relevance to Autism

Reynhout et al., 2018 reported 16 individuals with de novo variants in the PPP2CA gene who presented with syndromic developmental delay/intellectual disability; five of these individuals presented with ASD or PDD-NOS, while two other individuals presented with stereotypic behavior or movements.

Molecular Function

This gene encodes the phosphatase 2A catalytic subunit. Protein phosphatase 2A is one of the four major Ser/Thr phosphatases, and it is implicated in the negative control of cell growth and division. It consists of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit, that associates with a variety of regulatory subunits. This gene encodes an alpha isoform of the catalytic subunit.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PPP2CA (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De Novo Mutations Affecting the Catalytic C? Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders Reynhout S , et al. (2019) No ASD, epilepsy/seizures
2 Support - Pode-Shakked B et al. (2021) Yes -
3 Support - Zhou X et al. (2022) Yes -
4 Support - Verbinnen I et al. (2022) Yes -
5 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (21)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - Simplex 30595372 Reynhout S , et al. (2019)
c.572A>G p.His191Arg missense_variant De novo - - 30595372 Reynhout S , et al. (2019)
c.667G>C p.Asp223His missense_variant De novo - - 30595372 Reynhout S , et al. (2019)
c.794A>G p.Tyr265Cys missense_variant De novo - - 30595372 Reynhout S , et al. (2019)
c.586T>C p.Cys196Arg missense_variant De novo - - 36531959 Verbinnen I et al. (2022)
c.722A>G p.His241Arg missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.617G>T p.Arg206Leu missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.373C>T p.Gln125Ter stop_gained De novo - Simplex 30595372 Reynhout S , et al. (2019)
c.640C>T p.Arg214Ter stop_gained De novo - Simplex 30595372 Reynhout S , et al. (2019)
c.28C>T p.Leu10%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.179G>T p.Gly60Val missense_variant De novo - Simplex 30595372 Reynhout S , et al. (2019)
c.263A>G p.Asp88Gly missense_variant De novo - Simplex 30595372 Reynhout S , et al. (2019)
c.366G>C p.Gln122His missense_variant De novo - Simplex 30595372 Reynhout S , et al. (2019)
c.380A>G p.Tyr127Cys missense_variant De novo - Simplex 30595372 Reynhout S , et al. (2019)
c.391G>C p.Asp131His missense_variant De novo - Simplex 30595372 Reynhout S , et al. (2019)
c.572A>G p.His191Arg missense_variant De novo - Simplex 30595372 Reynhout S , et al. (2019)
c.668A>T p.Asp223Val missense_variant De novo - Simplex 30595372 Reynhout S , et al. (2019)
c.438del p.Phe146LeufsTer29 frameshift_variant De novo - - 30595372 Reynhout S , et al. (2019)
c.882dup p.Arg295Ter frameshift_variant De novo - Simplex 30595372 Reynhout S , et al. (2019)
c.667G>C p.Asp223His missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.923_924insTCT p.Phe308_Leu309insLeu inframe_insertion De novo - Simplex 30595372 Reynhout S , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Reynhout et al., 2018 reported 16 individuals with de novo variants in the PPP2CA gene who presented with syndromic developmental delay/intellectual disability; five of these individuals presented with ASD or PDD-NOS, while two other individuals presented with stereotypic behavior or movements.

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Reynhout et al., 2018 reported 16 individuals with de novo variants in the PPP2CA gene who presented with syndromic developmental delay/intellectual disability; five of these individuals presented with ASD or PDD-NOS, while two other individuals presented with stereotypic behavior or movements.

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.76536634184414

Ranking 21/25841 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 0.98550934793855

Ranking 1969/18225 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 0.91912039842136

Ranking 8943/18665 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 0.19083938197076

Ranking 4414/20870 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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