PPP2CA

Chr 5AD

protein phosphatase 2 catalytic subunit alpha

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

NCBI Gene: 5515ENSG00000113575UniProt: P67775

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]

Primary Disease Associations & Inheritance

Houge-Janssens syndrome 3MIM #618354
AD
298
ClinVar variants
57
Pathogenic / LP
0.99
pLI score· haploinsufficient
0
Active trials
Clinical Summary— PPP2CA
⚡
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.
📋
ClinVar Variants
57 Pathogenic / Likely Pathogenic· 87 VUS of 298 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.06 (0.02–0.26)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.13 (0.10–0.19)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.23
0≤1.21.6
LoF obs/exp: 1 / 18.1Missense obs/exp: 24 / 181.2Syn Z: -1.43

ClinVar Variant Classifications

298 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30
Likely Pathogenic27
VUS87
Likely Benign123
Benign9
Conflicting4
30
Pathogenic
27
Likely Pathogenic
87
VUS
123
Likely Benign
9
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
2
20
0
30
Likely Pathogenic
6
15
6
0
27
VUS
3
68
16
0
87
Likely Benign
0
4
49
70
123
Benign
0
2
6
1
9
Conflicting
—4
Total17919771280

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

View in ClinVar →

Protein Context — Lollipop Plot

PPP2CA · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

PPP2CA-related syndromic intellectual disability resembling other PP2A related neurodevelopmental disorders

strong
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Houge-Janssens syndrome 3

MIM #618354

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Houge-Janssens syndrome.
Houge GD et al.·Eur J Hum Genet
2025Review
Pathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum.
Verbinnen I et al.·Am J Hum Genet
2025
Association between PPP2CA expression and colorectal cancer prognosis tumor marker prognostic study.
Yong L et al.·Int J Surg
2018
E3 ligase MKRN2 destabilizes PPP2CA proteins to inactivate canonical Wnt pathway and mitigates tumorigenesis of clear cell renal cell carcinoma.
Yu T et al.·Int J Biol Sci
2025
Phillyrin for sepsis-related acute lung injury: A potential strategy suppressing GSK-3β.
Yang G et al.·Mol Immunol
2025
RCN2 facilitates esophageal squamous cellular carcinoma metastasis and cisplatin resistance through UBR5-mediated PPP2CA ubiquitination and degradation.
Wu M et al.·Drug Resist Updat
2026
Association between PPP2CA polymorphisms and clinical features in southwest Chinese systemic lupus erythematosus patients.
Zhang J et al.·Medicine (Baltimore)
2018Cohort
Gene-function studies in systemic lupus erythematosus.
Crispín JC et al.·Nat Rev Rheumatol
2013Review
Restoration of PPP2CA expression reverses epithelial-to-mesenchymal transition and suppresses prostate tumour growth and metastasis in an orthotopic mouse model.
Bhardwaj A et al.·Br J Cancer
2014Functional
PPP2CA Inhibition Promotes Ferroptosis Sensitivity Through AMPK/SCD1 Pathway in Colorectal Cancer.
Liang X et al.·Dig Dis Sci
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools