PPP2CA

protein-coding

protein phosphatase 2 catalytic subunit alpha, the group of Protein phosphatase catalytic subunits|STRIPAK complex

Gene summary

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]

MANE transcript

NM_002715.4

Inheritance

ClinVar variants

P:44U:89B:79

Top phenotype

Houge-Janssens syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr5:134,193,978-134,226,073

External References & Databases

Ensembl (ENSG00000113575)

Transcript & Mutation Effects

hg38 • Region Span ~32.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Houge-Janssens syndrome 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032697

Submitter: PanelApp Australia

Houge-Janssens syndrome 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032697

Submitter: Labcorp Genetics (formerly Invitae)

Houge-Janssens syndrome 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032697

Submitter: G2P

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

The *PPP2CA* gene encodes the α isoform of the catalytic subunit C of protein phosphatase 2A (PP2A), an intracellular serine/threonine phosphatase. *PPP2CA* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2019 (Reynhout et al., PMID: 30595372). The disorder is characterized by variable clinical features, including global developmental delay, mild to profound intellectual disability, hypotonia, autism spectrum disorder, seizures, and abnormalities on brain imaging, including enlarged ventricles, thin corpus callosum, and sometimes small brainstem. Some individuals may have microcephaly, macrocephaly, or nonspecific dysmorphic features. Nine variants (four missense, three nonsense, one frameshift, and one in-frame duplication) that have been reported in nine probands in two publications (PMIDs: 30595372, 36531959) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. All reported variants are *de novo*. The mechanism of pathogenicity is reported to be loss of function, arising from multiple mechanisms, such as loss of enzymatic activity and disruption of PP2A holoenzyme assembly by impairing interactions with the regulatory and scaffolding subunits. Additionally, variants in the C-terminal region of the protein, which is involved in methylation-dependent regulation and B subunit recruitment, are proposed to have a dominant-negative effect (PMID: 40555839). This gene-disease relationship is also supported by experimental evidence, including protein interaction and biochemical function. In the brain, PP2A phosphatases regulate cortical development, synaptic transmission, and hippocampus-dependent memory (PMID: 34241636). Pathogenic variants in other members of the protein phosphatase 2A gene family, *PPP2R1A*, *PPP2R5D*, and *PPP2R5C*, also cause neurodevelopmental disorders with overlapping phenotypes. In summary, there is definitive evidence supporting the relationship between *PPP2CA* and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 7, 2025 (SOP Version 11).

Houge-Janssens syndrome 3MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032697

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Houge-Janssens syndrome 3AD

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: 30595372

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PPP2CA variants in ClinVar

6 Conditions Cataloged

not providedTotal: 225

Houge-Janssens syndrome 3Total: 34

not specifiedTotal: 13

Inborn genetic diseasesTotal: 10

PPP2CA-related disorderTotal: 9

Prostate cancerTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002715.4. 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				71 clinvar	1 clinvar	72
missense	1 clinvar	18 clinvar	79 clinvar	5 clinvar	2 clinvar	105
nonsense	4 clinvar	4 clinvar				8
start loss	1 clinvar		1 clinvar			2
frameshift	8 clinvar	4 clinvar	1 clinvar			13
splice donor/acceptor (+/-2bp)	1 clinvar	3 clinvar	8 clinvar			12
Total	15	29	89	76	3	212

Highest pathogenic variant AF is 0.000006569784

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002715.4	RefSeq	NP_002706.1	7	MANE Select
ENST00000481195.6	Ensembl	ENSP00000418447.1	7	MANE Select
NM_001355019.2	RefSeq	NP_001341948.1	6	Standard
ENST00000522385.2	Ensembl	ENSP00000430869.2	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
TGF-beta signaling pathway - Homo sapiens (human)
Dopaminergic synapse - Homo sapiens (human)
Oocyte meiosis - Homo sapiens (human)
Long-term depression - Homo sapiens (human)

Biological Process

nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
inactivation of MAPK activity
regulation of protein phosphorylation
regulation of DNA replication
regulation of transcription, DNA-templated

Molecular Function

phosphoprotein phosphatase activity
protein serine/threonine phosphatase activity
protein binding
protein C-terminus binding
metal ion binding

Cellular Component

protein phosphatase type 2A complex
chromosome, centromeric region
spindle pole
nucleus
mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000481195
Coding exons: 7
Length: 31809
Individuals with no LoFs: 123598
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 123600
p: 0.00000809

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.15	24	181	0.132	0.0000100	2021
Missense (PolyPhen)		1	65.33	0.015307		800
Synonymous	-1.43	75	60.8	1.23	0.00000307	584
Loss of Function	3.72	1	18.1	0.0554	9.63e-7	198

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000090	0.0000090	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: PP2A is the major phosphatase for microtubule-associated proteins (MAPs). PP2A can modulate the activity of phosphorylase B kinase casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2 kinase. Cooperates with SGO2 to protect centromeric cohesin from separase-mediated cleavage in oocytes specifically during meiosis I (By similarity). Can dephosphorylate SV40 large T antigen and p53/TP53. Activates RAF1 by dephosphorylating it at 'Ser-259'. {ECO:0000250, ECO:0000269|PubMed:10801873, ECO:0000269|PubMed:22613722, ECO:0000269|PubMed:9920888}.;

Recessive Scores

pRec: 0.292

Intolerance Scores

RVIS EVS: -0.25
RVIS percentile EVS: 35.42

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.931