PPP2R1A

Chr 19AD

protein phosphatase 2 scaffold subunit Aalpha

Also known as: HJS2, MRD36, PP2A-Aalpha, PP2AA, PP2AAALPHA, PR65A

NCBI Gene: 5518 ENSG00000105568 UniProt: P30153 OMIM: 605983

The protein serves as a scaffolding subunit that coordinates assembly of protein phosphatase 2, a major serine/threonine phosphatase involved in negative control of cell growth and division. Mutations cause Houge-Janssens syndrome 2, inherited in an autosomal dominant pattern. The high pLI score (0.98) and low LOEUF score (0.30) indicate the gene is highly intolerant to loss-of-function variants, suggesting haploinsufficiency as the likely pathogenic mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a constant regulatory subunit of protein phosphatase 2. Protein phosphatase 2 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. The constant regulatory subunit A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit. This gene encodes an alpha isoform of the constant regulatory subunit A. Alternatively spliced transcript variants have been described. [provided by RefSeq, Apr 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismADLOEUF 0.301 OMIM phenotype

Clinical Summary— PPP2R1A

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · 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 0.98). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

20 unique Pathogenic / Likely Pathogenic· 208 VUS of 646 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PPP2R1A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.30LOEUF

pLI 0.984

Z-score 4.42

OE 0.13 (0.06–0.30)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

4.46Z-score

OE missense 0.34 (0.29–0.40)

123 obs / 361.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.13 (0.06–0.30)

0≤0.351.4

Missense OE?0.34 (0.29–0.40)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 4 / 30.2Missense obs/exp: 123 / 361.4Syn Z: 0.55

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePPP2R1A-related intellectual disabilityDNAD

This gene — mechanism propensity

0.5476th %ile

GOF

0.5464th %ile

LOF

0.59top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). 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.

LOFLOEUF 0.30

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNMutant B56d was A and C binding-deficient, while mutant Aa subunits bound B56d well but were unable to bind C or bound a catalytically impaired C, suggesting a dominant-negative effect where mutant subunits hinder dephosphorylation of B56d-anchored substrates.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 26168268 ↗

ClinVar Variant Classifications

646 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic15

VUS208

Likely Benign325

Benign36

Conflicting21

Pathogenic

Likely Pathogenic

208

VUS

325

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	4	0	0	5
Likely Pathogenic	0	15	0	0	15
VUS	5	182	17	4	208
Likely Benign	0	15	136	174	325
Benign	0	16	14	6	36
Conflicting	—				21
Total	6	232	167	184	610

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap PPP2R1A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →