PPP2R5C

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0978293

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

The *PPP2R5C* gene encodes the B56δ regulatory subunit of protein phosphatase 2A (PP2A), an intracellular serine/threonine phosphatase. *PPP2R5C* was first described in relation to autosomal dominant complex neurodevelopmental disorder as a candidate gene in 2015 (Loveday et al., PMID: 25972378), and reported as a disease gene in 2025 (Verbinnen et al., PMID: 39978342). The disorder is characterized by global developmental delay, hypotonia, delayed walking, variably impaired intellectual development, behavioral abnormalities (including autism spectrum disorder), and poor or absent speech. Most affected individuals have a large head circumference or macrocephaly, and about half have dysmorphic facial features. About half of patients have seizures. Twelve *de novo* variants (missense and in-frame deletions) reported in 12 probands in two publications (PMIDs: 25533962, 39978342) are included in this curation. More evidence is available in the literature (PMID: 39696819), but the maximum score for genetic evidence (12 points) has been reached. Several variants are recurrent, including p.Gly122Lys reported in four unrelated individuals. Most reported *PPP2R5C* variants cluster within a highly conserved acidic loop of the B56γ regulatory subunit that interfaces with the PP2A A (scaffolding) and C (catalytic) subunits. Functional studies demonstrate that the majority of variants impair A- and/or C-subunit binding, frequently accompanied by reduced substrate binding and phosphatase activity, consistent with disruption of PP2A-B56γ–mediated substrate dephosphorylation (PMID: 39978342). While five cases of heterozygous loss-of-function *PPP2R5C* variants have been reported (PMID: 39978342), they were not included in the curation because the role of loss-of-function variants as a disease mechanism is unclear at this time. Indeed, loss-of-function variants have been observed in apparently unaffected individuals, and may be inherited from an unaffected parent. These observations argue against haploinsufficiency and suggest a dominant-negative disease mechanism for missense and in-frame variants (PMID: 39978342). This gene-disease relationship is also supported by experimental evidence, including protein interaction and biochemical function. Pathogenic variants in other members of the protein phosphatase 2A gene family, *PPP2R1A*, *PPP2CA* and *PPP2R5D*, also cause neurodevelopmental disorders with overlapping phenotypes. In summary, there is definitive evidence to support the relationship between *PPP2R5C* and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 16, 2025 (SOP Version 11).