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

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. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

42 unique Pathogenic / Likely Pathogenic· 84 VUS of 279 total submissions

Explore recent and relevant literature in Research Assistant →

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 OE?0.06 (0.02–0.26)

0≤0.351.4

Missense OE?0.13 (0.10–0.19)

0≤0.61.4

Synonymous OE?1.23

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

This gene — mechanism propensity

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 · 55% of P/LP variants are LoF · 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 PP2A1

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.1

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

References

1.PMID 30595372 ↗

ClinVar Variant Classifications

279 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

Likely Pathogenic27

VUS84

Likely Benign122

Benign9

Conflicting4

Pathogenic

Likely Pathogenic

VUS

122

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	13	2	0	0	15
Likely Pathogenic	10	17	0	0	27
VUS	3	73	8	0	84
Likely Benign	0	4	48	70	122
Benign	0	2	6	1	9
Conflicting	—				4
Total	26	98	62	71	261

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

16 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap PPP2CA — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →