PPP3CA

Chr 4AD

protein phosphatase 3 catalytic subunit alpha

Also known as: ACCIID, CALN, CALNA, CALNA1, CNA1, DEE91, IECEE, IECEE1

NCBI Gene: 5530 ENSG00000138814 UniProt: Q08209 OMIM: 114105

The protein is a calcium-dependent, calmodulin-stimulated phosphatase that dephosphorylates multiple substrates involved in transcription, mitochondrial dynamics, and cellular signaling pathways. Mutations cause developmental and epileptic encephalopathy 91 as well as arthrogryposis with cleft palate, craniosynostosis, and intellectual disability, inherited in an autosomal dominant pattern. This gene is extremely intolerant to loss-of-function variants (pLI=1.0, LOEUF=0.16), indicating that even single functional copies are insufficient for normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.162 OMIM phenotypes

Clinical Summary— PPP3CA

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Gene-Disease Validity (ClinGen)

developmental and epileptic encephalopathy · 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 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

26 unique Pathogenic / Likely Pathogenic· 106 VUS of 300 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.16LOEUF

pLI 1.000

Z-score 4.91

OE 0.03 (0.01–0.16)

Highly constrained

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

Missense Constraint

3.63Z-score

OE missense 0.39 (0.34–0.46)

112 obs / 283.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.03 (0.01–0.16)

0≤0.351.4

Missense OE0.39 (0.34–0.46)

0≤0.61.4

Synonymous OE0.99

0≤1.21.6

LoF obs/exp: 1 / 30.1Missense obs/exp: 112 / 283.9Syn Z: 0.08

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongPPP3CA-related severe neurodevelopmental disease with seizuresOTHERAD

0.3097th %ile

GOF

0.4776th %ile

LOF

0.73top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). 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 · 46% of P/LP variants are LoF · LOEUF 0.16

GOF1 literature citation

Literature Evidence

GOFLoss-of-function and gain-of-function mutations in PPP3CA cause two distinct disorders.PMID:29432562

LOFLoss-of-function and gain-of-function mutations in PPP3CA cause two distinct disorders.PMID:29432562

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