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

Enables several functions, including ATPase binding activity; calmodulin binding activity; and calmodulin-dependent protein phosphatase activity. Involved in several processes, including calcineurin-NFAT signaling cascade; negative regulation of angiotensin-activated signaling pathway; and peptidyl-serine dephosphorylation. Located in cytoplasm; cytoplasmic side of plasma membrane; and dendritic spine. Part of calcineurin complex. Implicated in developmental and epileptic encephalopathy 91. Biomarker of cholangiocarcinoma; focal segmental glomerulosclerosis; and schizophrenia. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

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

50 unique Pathogenic / Likely Pathogenic· 242 VUS of 618 total submissions

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Clinical Trials

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

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?

0.16LOEUF

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 OE?0.03 (0.01–0.16)

0≤0.351.4

Missense OE?0.39 (0.34–0.46)

0≤0.61.4

Synonymous OE?0.99

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

This gene — mechanism propensity

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 · 58% 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.1

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

ClinVar Variant Classifications

618 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23

Likely Pathogenic27

VUS242

Likely Benign265

Benign31

Conflicting8

Pathogenic

Likely Pathogenic

242

VUS

265

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	17	6	0	0	23
Likely Pathogenic	12	15	0	0	27
VUS	5	201	31	5	242
Likely Benign	1	5	114	145	265
Benign	0	0	27	4	31
Conflicting	—				8
Total	35	227	172	154	596

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap PPP3CA — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →