PPP3CA

protein-coding

protein phosphatase 3 catalytic subunit alpha, the group of MicroRNA protein coding host genes|Protein phosphatase catalytic subunits

Gene summary

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]

Previous symbols:

CALN
CALNA

MANE transcript

NM_000944.5

Inheritance

ClinVar variants

P:52U:225B:165

Top phenotype

Developmental and epileptic encephalopathy 91; Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chr4:101,023,409-101,348,278

External References & Databases

Ensembl (ENSG00000138814)

Transcript & Mutation Effects

hg38 • Region Span ~324.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy 91MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0020630

Submitter: Ambry Genetics

arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual developmentLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0032642

Submitter: Ambry Genetics

developmental and epileptic encephalopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100620

Submitter: ClinGen

*PPP3CA* (protein phosphatase 3 catalytic subunit alpha) encodes the catalytic A-subunit of calcineurin (CaN), a calcium/calmodulin-regulated serine–threonine phosphatase that plays a critical role in neuronal signalling, synaptic plasticity, and brain development. The gene comprises 14 exons and encodes a protein with five functional regions: the catalytic domain (CD), calcineurin regulatory subunit–binding domain (CnBB), calmodulin-binding domain (CaMB), regulatory domain (RD), and autoinhibitory domain (AID). Published data support distinct *PPP3CA*-associated phenotypic groups, driven by variant mechanisms and affecting different protein domains: Developmental and epileptic encephalopathy (DEE91), most often associated with loss-of-function missense or truncating variants clustering in the regulatory domain, and ACCIID (arthrogryposis, cleft palate, craniosynostosis, impaired intellectual development), most often associated with gain-of-function variants affecting the autoinhibitory domain. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanism and phenotypic variability. Therefore, the following disease entities have been split: AD developmental and epileptic encephalopathy 91 (OMIM: 617711) and Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (OMIM: 618265). The gain of function variants will be assessed separately. Pathogenic variants in *PPP3CA* were first reported in 2017 in individuals with severe neurodevelopmental disorders associated with developmental and epileptic encephalopathy (DEE) (PMID: 28942967). Individuals with DEE typically present with early-onset epilepsy, most commonly infantile epileptic spasms syndrome (IESS/West syndrome), which often evolves into multiple seizure types and shows marked pharmacoresistance. Neurological features include global developmental delay, frequently severe to profound intellectual disability, hypotonia, and characteristic EEG abnormalities such as hypsarrhythmia or multifocal/generalised epileptiform discharges. Across 10 independent publications and cohorts reported between 2017 and 2025, a total of 24 unique variants have been described, including missense, nonsense, frameshift, and structural rearrangements in unrelated individuals (PMIDs: 28942967, 29432562, 30455226, 30951195, 32593294, 33963760, 36158964, 39305655, 39707491, 40548073). Most variants were de novo, with at least 10 variants observed in more than one unrelated individual. Truncating variants appear to cluster within a narrow region of the regulatory domain, between the calmodulin-binding domain and the autoinhibitory domain, which is consistently associated with particularly severe DEE phenotypes. This gene-disease relationship is supported by functional and expression studies, reported alongside case-level data, further supporting domain-dependent pathogenic mechanisms, providing strong biological plausibility for the observed clinical phenotypes . In summary, there is definitive evidence to support the relationship between *PPP3CA* and autosomal dominant developmental and epileptic encephalopathy (DEE). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date December 16, 2025 (SOP Version 11).

arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual developmentSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032642

Submitter: Labcorp Genetics (formerly Invitae)

arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual developmentSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032642

Submitter: PanelApp Australia

developmental and epileptic encephalopathy 91STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020630

Submitter: PanelApp Australia

developmental and epileptic encephalopathy 91STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020630

Submitter: Labcorp Genetics (formerly Invitae)

arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual developmentSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0032642

Submitter: Orphanet

developmental and epileptic encephalopathy 91STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020630

Submitter: G2P

undetermined early-onset epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018614

Submitter: Orphanet

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 91; Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual developmentAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 28942967; 29432562

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PPP3CA variants in ClinVar

12 Conditions Cataloged

not providedTotal: 516

Developmental and epileptic encephalopathy 91Total: 86

Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual developmentTotal: 59

not specifiedTotal: 40

Inborn genetic diseasesTotal: 28

PPP3CA-related disorderTotal: 21

SeizureTotal: 2

See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000944.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	152 clinvar	3 clinvar	161
missense	6 clinvar	17 clinvar	211 clinvar	9 clinvar		243
nonsense	2 clinvar	2 clinvar	3 clinvar			7
start loss						0
frameshift	13 clinvar	7 clinvar	2 clinvar	1 clinvar		23
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar	3 clinvar			8
Total	22	30	225	162	3	442

Highest pathogenic variant AF is 0.0000023627517

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000944.5	RefSeq	NP_000935.1	14	MANE Select
ENST00000394854.8	Ensembl	ENSP00000378323.3	14	MANE Select
NM_001130691.2	RefSeq	NP_001124163.1	13	Standard
NM_001130692.2	RefSeq	NP_001124164.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Oxytocin signaling pathway - Homo sapiens (human)
T cell receptor signaling pathway - Homo sapiens (human)
B cell receptor signaling pathway - Homo sapiens (human)
Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
VEGF signaling pathway - Homo sapiens (human)

Biological Process

G1/S transition of mitotic cell cycle
response to amphetamine
protein dephosphorylation
protein import into nucleus
calcium ion transport

Molecular Function

protein serine/threonine phosphatase activity
calcium ion binding
protein binding
calmodulin binding
drug binding

Cellular Component

nucleoplasm
cytoplasm
mitochondrion
cytosol
calcineurin complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000394854
Coding exons: 14
Length: 324870
Individuals with no LoFs: 120544
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 120548
p: 0.0000166

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.63	112	284	0.394	0.0000147	3436
Missense (PolyPhen)		16	104.04	0.15379		1251
Synonymous	0.0834	101	102	0.990	0.00000523	961
Loss of Function	4.91	1	30.1	0.0333	0.00000167	363

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00014	0.00013	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals (PubMed:15671020, PubMed:18838687, PubMed:19154138, PubMed:23468591). Many of the substrates contain a PxIxIT motif and/or a LxVP motif (PubMed:17498738, PubMed:17502104, PubMed:23468591, PubMed:27974827, PubMed:22343722). In response to increased Ca(2+) levels, dephosphorylates and activates phosphatase SSH1 which results in cofilin dephosphorylation (PubMed:15671020). In response to increased Ca(2+) levels following mitochondrial depolarization, dephosphorylates DNM1L inducing DNM1L translocation to the mitochondrion (PubMed:18838687). Dephosphorylates heat shock protein HSPB1 (By similarity). Dephosphorylates and activates transcription factor NFATC1 (PubMed:19154138). In response to increased Ca(2+) levels, regulates NFAT-mediated transcription probably by dephosphorylating NFAT and promoting its nuclear translocation (PubMed:26248042). Dephosphorylates and inactivates transcription factor ELK1 (PubMed:19154138). Dephosphorylates DARPP32 (PubMed:19154138). {ECO:0000250|UniProtKB:P48452, ECO:0000269|PubMed:15671020, ECO:0000269|PubMed:17498738, ECO:0000269|PubMed:17502104, ECO:0000269|PubMed:18838687, ECO:0000269|PubMed:19154138, ECO:0000269|PubMed:22343722, ECO:0000269|PubMed:23468591, ECO:0000269|PubMed:26248042, ECO:0000269|PubMed:27974827}.;
Disease: DISEASE: Epileptic encephalopathy, infantile or early childhood, 1 (IECEE1) [MIM:617711]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. IECEE1 is an autosomal dominant condition with onset of seizures between the first weeks and first years of life. {ECO:0000269|PubMed:28942967}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.303

Intolerance Scores

LoFtool: 0.0811
RVIS EVS: -0.43
RVIS percentile EVS: 25.15

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.945

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium