PPP2CA

Chr 5AD

protein phosphatase 2 catalytic subunit alpha

Also known as: HJS3, NEDLBA, PP2Ac, PP2CA, PP2Calpha, RP-C

NCBI Gene: 5515 ENSG00000113575 UniProt: P67775 OMIM: 176915

The protein phosphatase 2A catalytic subunit alpha isoform dephosphorylates serine and threonine residues to negatively regulate cell growth and division as part of a heteromeric phosphatase complex. Loss-of-function mutations cause Houge-Janssens syndrome 3, inherited in an autosomal dominant pattern. The gene is highly intolerant to loss-of-function variation, indicating haploinsufficiency as the likely pathogenic mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

LOFmechanismADLOEUF 0.261 OMIM phenotype

Clinical Summary— PPP2CA

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.26LOEUF

pLI 0.989

Z-score 3.72

OE 0.06 (0.02–0.26)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

4.15Z-score

OE missense 0.13 (0.10–0.19)

24 obs / 181.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.06 (0.02–0.26)

0≤0.351.4

Missense OE0.13 (0.10–0.19)

0≤0.61.4

Synonymous OE1.23

0≤1.21.6

LoF obs/exp: 1 / 18.1Missense obs/exp: 24 / 181.2Syn Z: -1.43

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongPPP2CA-related syndromic intellectual disability resembling other PP2A related neurodevelopmental disordersLOFAD

0.4586th %ile

GOF

0.4382th %ile

LOF

0.67top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.26

DN1 literature citation

Literature Evidence

DNFour were suspected to have a dominant-negative mechanism, which correlated with severe ID. Two missense variants affecting the same residue largely behaved as wild-type in our functional assays. Overall, we found that pathogenic PPP2CA variants impair PP2A-B56(d) functionality, suggesting that PP2APMID:30595372

LOFSeveral PPP2CA mutations were predicted to result in nonfunctional alleles, and in vitro studies of HEK293 cells transfected with selected mutations, including missense variants, confirmed decreased or absent protein levels, consistent with haploinsufficiency as the main pathogenic mechanism.PMID:30595372

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.