PPP2R5D

Chr 6AD

protein phosphatase 2 regulatory subunit B'delta

Also known as: B56D, B56delta, HJS1, MRD35

NCBI Gene: 5528 ENSG00000112640 UniProt: Q14738 OMIM: 601646

The protein is a regulatory subunit of protein phosphatase 2A that modulates substrate selectivity and catalytic activity of this major serine/threonine phosphatase involved in controlling cell growth and division. Loss-of-function mutations cause Houge-Janssens syndrome 1, an autosomal dominant neurodevelopmental disorder. The gene is highly intolerant to loss-of-function variants, indicating haploinsufficiency as the likely disease mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

DNmechanismADLOEUF 0.171 OMIM phenotype

Clinical Summary— PPP2R5D

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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 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.17LOEUF

pLI 1.000

Z-score 5.24

OE 0.06 (0.02–0.17)

Highly constrained

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

Missense Constraint

3.65Z-score

OE missense 0.45 (0.39–0.51)

155 obs / 345.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.06 (0.02–0.17)

0≤0.351.4

Missense OE0.45 (0.39–0.51)

0≤0.61.4

Synonymous OE0.97

0≤1.21.6

LoF obs/exp: 2 / 35.9Missense obs/exp: 155 / 345.9Syn Z: 0.26

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePPP2R5D-related intellectual disabilityDNAD

0.4586th %ile

GOF

0.3392th %ile

LOF

0.70top 10%

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.

LOFprediction above median · LOEUF 0.17

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

DNIn vitro functional expression studies in HEK293 cells showed that all mutations, except P53S, showed deficient holoenzyme formation of PP2A with decreased association of the mutant PPP2R5D subunit to the A or C subunits, consistent with a dominant-negative effect.PMID:26168268

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.