Human Gene Module / Chromosome 14 / PPP2R5C

PPP2R5Cprotein phosphatase 2 regulatory subunit B'gamma

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
3 / 5
Rare Variants / Common Variants
25 / 1
Aliases
-
Associated Syndromes
-
Chromosome Band
14q32.31
Associated Disorders
-
Relevance to Autism

Verbinnen et al., 2025 described a cohort of 26 individuals with predominantly de novo missense variants in the PPP2R5C gene who presented with a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum characterized by neurodevelopmental delay and hypotonia with a high risk of epilepsy, behavioral problems, macrocephaly, and mildly dysmorphic facial features; 5 individuals in this cohort were reported to have been diagnosed with autism spectrum disorder. Additional biochemical assessment of PPP2R5C variants reported in Verbinnen et al., 2025 demonstrated defects in subunit binding, substrate binding, and/or phosphatase catalytic activity. Muir et al., 2024 had previously reported a recurrent missense variant in PPP2R5C (NM_001161725.2:c.457G>A;p.Glu153Lys) in five unrelated individuals with overlapping clinical features of macrocephaly, intellectual disability, and seizures; detailed clinical summaries of two of the five individuals with this recurrent missense variant reported one individual with autism spectrum disorder. De novo missense variants in PPP2R5C that were predicted to be damaging (CADD > 25) were also reported in an ASD proband from the SAGE cohort (Guo et al., 2019) and in a male ASD proband from the SPARK cohort (Feliciano et al., 2019). Association analysis of ASD families from the Autism Genome Project (AGP) Consortium in Anney et al., 2010 identified an intronic SNP in the PPP2R5C gene (rs7142002) as fulfilling the threshold for association with ASD (P < 5.0E-06).

Molecular Function

The product of this gene belongs to the phosphatase 2A regulatory subunit B family. 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. The B regulatory subunit might modulate substrate selectivity and catalytic activity. This gene encodes a gamma isoform of the regulatory subunit B56 subfamily.

External Links
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Reports related to PPP2R5C (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Positive association A genome-wide scan for common alleles affecting risk for autism Anney R , et al. (2010) Yes -
2 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
3 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
4 Support - Alison M Muir et al. () No ASD, DD
5 Primary - Iris Verbinnen et al. (2025) No ASD, ADHD, epilepsy/seizures
Rare Variants   (25)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.457G>A p.Glu153Lys missense_variant Unknown - - 39696819 Alison M Muir et al. ()
c.848C>T p.Leu283Ser missense_variant De novo - Simplex 30504930 Guo H , et al. (2018)
c.310T>C p.Cys104Arg missense_variant De novo - - 39978342 Iris Verbinnen et al. (2025)
c.330T>A p.Phe110Leu missense_variant De novo - - 39978342 Iris Verbinnen et al. (2025)
c.524C>G p.Pro175Arg missense_variant De novo - - 39978342 Iris Verbinnen et al. (2025)
c.529G>A p.Glu177Lys missense_variant De novo - - 39978342 Iris Verbinnen et al. (2025)
c.535G>A p.Glu179Lys missense_variant De novo - - 39978342 Iris Verbinnen et al. (2025)
c.556T>C p.Trp186Arg missense_variant De novo - - 39978342 Iris Verbinnen et al. (2025)
c.556T>C p.Trp186Arg missense_variant Unknown - - 39978342 Iris Verbinnen et al. (2025)
c.563A>C p.His188Pro missense_variant De novo - - 39978342 Iris Verbinnen et al. (2025)
c.563A>G p.His188Arg missense_variant De novo - - 39978342 Iris Verbinnen et al. (2025)
c.563A>T p.His188Leu missense_variant De novo - - 39978342 Iris Verbinnen et al. (2025)
c.566T>C p.Leu189Pro missense_variant De novo - - 39978342 Iris Verbinnen et al. (2025)
c.685G>A p.Glu229Lys missense_variant De novo - - 39978342 Iris Verbinnen et al. (2025)
c.689A>T p.Asp230Val missense_variant De novo - - 39978342 Iris Verbinnen et al. (2025)
c.694C>T p.Arg232Trp missense_variant De novo - - 39978342 Iris Verbinnen et al. (2025)
c.695G>T p.Arg232Leu missense_variant Unknown - - 39978342 Iris Verbinnen et al. (2025)
c.895A>G p.Lys299Glu missense_variant De novo - - 39978342 Iris Verbinnen et al. (2025)
c.1080A>C p.Leu360Phe missense_variant Unknown - - 39978342 Iris Verbinnen et al. (2025)
c.1195G>A p.Glu399Lys missense_variant De novo - - 39978342 Iris Verbinnen et al. (2025)
c.457G>A p.Glu153Lys missense_variant De novo - Simplex 39696819 Alison M Muir et al. ()
c.416G>A p.Arg139Gln missense_variant De novo - Simplex 31452935 Feliciano P et al. (2019)
c.540_542del p.Thr181del inframe_deletion De novo - - 39978342 Iris Verbinnen et al. (2025)
c.552_554del p.Ala185del inframe_deletion De novo - - 39978342 Iris Verbinnen et al. (2025)
c.326_331del p.Asp109_Phe110del inframe_deletion De novo - - 39978342 Iris Verbinnen et al. (2025)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.964-99T>C - intron_variant - - - 20663923 Anney R , et al. (2010)
SFARI Gene score
3S

Suggestive Evidence, Syndromic

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.

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."

4/1/2025
3S

Initial score established: 3S

Krishnan Probability Score

Score 0.57391421751029

Ranking 681/25841 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 0.99767266348225

Ranking 1298/18225 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 0.93268362923132

Ranking 12050/18665 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 -0.68749817954354

Ranking 20306/20870 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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