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.

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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)
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