PPP2R5D

Chr 6

protein phosphatase 2 regulatory subunit B'delta

Also known as: B56D, B56delta, HJS1, MRD35

NCBI Gene: 5528 ENSG00000112640 UniProt: Q14738

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.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The product of this gene belongs to the phosphatase 2A regulatory subunit B family. 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. The B regulatory subunit might modulate substrate selectivity and catalytic activity. This gene encodes a delta isoform of the regulatory subunit B56 subfamily. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

GeneReviews ResearchGenerating clinical summary…

DNmechanismLOEUF 0.17

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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ClinVar Variants

28 unique Pathogenic / Likely Pathogenic· 292 VUS of 676 total submissions

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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 →

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GeneReview available — PPP2R5D

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.06 (0.02–0.17)

0≤0.351.4

Missense OE?0.45 (0.39–0.51)

0≤0.61.4

Synonymous OE?0.97

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

This gene — mechanism propensity

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.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

676 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12

Likely Pathogenic16

VUS292

Likely Benign269

Benign32

Conflicting28

Pathogenic

Likely Pathogenic

292

VUS

269

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	11	0	0	12
Likely Pathogenic	0	15	1	0	16
VUS	16	249	23	4	292
Likely Benign	3	5	133	128	269
Benign	0	2	27	3	32
Conflicting	—				28
Total	20	282	184	135	649

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap PPP2R5D — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →