PTPA

protein-coding

protein phosphatase 2 phosphatase activator, the group of Cyclophilin peptidylprolyl isomerases|Protein phosphatase 2 modulatory subunits

Gene summary

Protein phosphatase 2A (PP2A) is one of the four major Ser/Thr phosphatases and is implicated in the negative control of cell growth and division. The core PP2A holoenzyme is a heterotrimer of a structural A subunit, a catalytic C subunit, and one of several regulatory B subunits, which are grouped into distinct families (B/PR55, B'/PR61, B''/PR72) that confer different substrate specificities and localizations. This gene, PTPA, does not encode one of these conventional B-type regulatory subunits. Rather, this PTPA gene encodes a peptidyl-prolyl cis-trans isomerase that acts as a Mg-ion and ATP-dependent activation chaperone, transiently engaging the PP2A A-C core dimer to restore its catalytic activity, including a distinct phosphotyrosyl phosphatase activity. Unlike classic B-family subunits, which dock stably onto the holoenzyme to alter its specificity, PTPA dissociates after activation rather than remaining a permanent structural component. PTPA was historically classified within the B' family, but this reflects an older nomenclature scheme rather than its actual mechanism, which is now understood to be that of a dedicated activator rather than a structural regulatory subunit. Note that PP2A was used as a symbol for this gene in early publications when its distinct chaperone function was not yet clearly distinguished from the holoenzyme it regulates. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2026]

Previous symbols:

PPP2R4

MANE transcript

NM_178000.3

Inheritance

AD, AR

ClinVar variants

P:2U:17B:8

Top phenotype

Parkinson disease 25, autosomal recessive early-onset, with impaired intellectual development

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr9:129,110,950-129,148,946

External References & Databases

Ensembl (ENSG00000119383)

Transcript & Mutation Effects

hg38 • Region Span ~38.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Parkinson diseaseMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0005180

Submitter: PanelApp Australia

Parkinson disease 25, autosomal recessive early-onset, with impaired intellectual developmentMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0957576

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Parkinson disease 25, autosomal recessive early-onset, with impaired intellectual developmentAR

Manifestation: Neurologic

Intervention: Neurologic

Rationale: Levodopa has been described as beneficial in individuals with Parkinson disease

Refs: 36073231

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PTPA variants in ClinVar

3 Conditions Cataloged

not providedTotal: 12

not specifiedTotal: 4

Parkinson disease 25, autosomal recessive early-onset, with impaired intellectual developmentTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_178000.3. 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			2 clinvar	4 clinvar	1 clinvar	7
missense	2 clinvar		8 clinvar		3 clinvar	13
nonsense			4 clinvar			4
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	2	0	17	4	4	27

Highest pathogenic variant AF is 0.0000028169172

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_178000.3	RefSeq	NP_821067.1	10	MANE Select
ENST00000393370.7	Ensembl	ENSP00000377036.2	10	MANE Select
NM_001193397.2	RefSeq	NP_001180326.1	9	Standard
NM_001271832.2	RefSeq	NP_001258761.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Insulin resistance - Homo sapiens (human)
miR-targeted genes in epithelium - TarBase
miR-targeted genes in leukocytes - TarBase
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in muscle cell - TarBase

Biological Process

protein peptidyl-prolyl isomerization
mitotic spindle organization
negative regulation of phosphoprotein phosphatase activity
positive regulation of phosphoprotein phosphatase activity
positive regulation of protein dephosphorylation

Molecular Function

peptidyl-prolyl cis-trans isomerase activity
signaling receptor binding
protein binding
ATP binding
protein tyrosine phosphatase activator activity

Cellular Component

protein phosphatase type 2A complex
nucleus
nucleoplasm
cytoplasm
calcium channel complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000393370
Coding exons: 10
Length: 37997
Individuals with no LoFs: 125742
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125747
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.69	124	190	0.654	0.0000107	2127
Missense (PolyPhen)		22	68.001	0.32352		752
Synonymous	-0.322	79	75.4	1.05	0.00000477	611
Loss of Function	3.76	1	18.4	0.0543	7.84e-7	219

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Acts as a regulatory subunit for serine/threonine- protein phosphatase 2A (PP2A) modulating its activity or substrate specificity, probably by inducing a conformational change in the catalytic subunit, a proposed direct target of the PPIase. Can reactivate inactive phosphatase PP2A-phosphatase methylesterase complexes (PP2A(i)) in presence of ATP and Mg(2+) (By similarity). Reversibly stimulates the variable phosphotyrosyl phosphatase activity of PP2A core heterodimer PP2A(D) in presence of ATP and Mg(2+) (in vitro). The phosphotyrosyl phosphatase activity is dependent of an ATPase activity of the PP2A(D):PPP2R4 complex. Is involved in apoptosis; the function appears to be independent from PP2A. {ECO:0000250, ECO:0000269|PubMed:16916641, ECO:0000269|PubMed:17333320}.;

Recessive Scores

pRec: 0.353

Intolerance Scores

RVIS EVS: -0.01
RVIS percentile EVS: 53.51

Essentials

Essential (gene trap): E