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 positive regulation of transcription by RNA polymerase II. Located in cytoplasmic side of plasma membrane; cytosol; 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, Jun 2026]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual developmentMIM #618265

Developmental and epileptic encephalopathy 91MIM #617711

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · developmental and epileptic encephalopathy · AD · ClinGen 2025

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.16

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in PPP3CA?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 360

345 rare PASS variants

Rare truncating (LoF)

1 in 13,000

29 rare PASS variants

Rare synonymous (reference)

1 in 200

251 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PPP3CA. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 400	1 in 17,000
South Asian	~43k	1 in 480	≈ 1 in 12,000
Remaining (unassigned)	~30k	1 in 280	none seen
European (Finnish)	~27k	1 in 1,100	≈ 1 in 12,000
Admixed American	~22k	1 in 530	1 in 3,300
African / African American	~21k	1 in 370	≈ 1 in 9,200
East Asian	~20k	1 in 310	none seen
Ashkenazi Jewish	~13k	1 in 2,100	≈ 1 in 13,000
Middle Eastern	~2,884	≈ 1 in 960	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 12 of 14 coding exons well covered in gnomAD exomes; exons 4, 8 marginal. Genomes: all 14.? see exons ↓