PPP2R5D

protein-coding

protein phosphatase 2 regulatory subunit B'delta, the group of Armadillo like helical domain containing|Protein phosphatase 2 regulatory subunits

Gene summary

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]

MANE transcript

NM_006245.4

Inheritance

ClinVar variants

P:32U:293B:157

Top phenotype

Hogue-Janssens syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr6:42,984,553-43,012,342

External References & Databases

Ensembl (ENSG00000112640)

Transcript & Mutation Effects

hg38 • Region Span ~27.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Houge-Janssens syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014602

Submitter: PanelApp Australia

Houge-Janssens syndrome 1SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014602

Submitter: Orphanet

Houge-Janssens syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014602

Submitter: Ambry Genetics

Houge-Janssens syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014602

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

The *PPP2R5D* gene encodes the B56δ regulatory subunit of protein phosphatase 2A (PP2A), an intracellular serine/threonine phosphatase. *PPP2R5D* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2015 (Deciphering Developmental Disorders Study, PMID: 25533962). The disorder is characterized by hypotonia, developmental delay, mild to severe intellectual disability, speech impairment, and macrocephaly. Other features present in some individuals include autism spectrum disorder, seizures, ophthalmologic abnormalities, mild dysmorphic facial features, brain MRI abnormalities, and early-onset parkinsonism. Seven missense variants that have been reported in 21 probands in four publications (PMIDs: 25533962, 25972378, 26168268, 26576547) are included in this curation. Most variants are *de novo*, and three are recurrent, with p.Glu198Lys present in 10 unrelated individuals and p.Glu200Lys present in four. Most of the reported variants cluster in a highly conserved acidic loop of the protein that faces the PP2A A and C subunits, and exhibit A and C binding defects, disrupting B56δ-dependent dephosphorylation dynamics (PMIDs: 26168268, 36216457). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is reported to be dominant negative. This gene-disease relationship is also supported by experimental evidence, including protein interaction and biochemical function. Pathogenic variants in other members of the protein phosphatase 2A gene family, *PPP2R1A*, *PPP2CA* and *PPP2R5C*, also cause neurodevelopmental disorders with overlapping phenotypes. In summary, there is definitive evidence to support the relationship between *PPP2R5D* 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 gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 26, 2021. It was reevaluated on April 16, 2025 (SOP Version 11). Although new experimental evidence was added, the classification did not change.

Houge-Janssens syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014602

Submitter: G2P

Houge-Janssens syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014602

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Hogue-Janssens syndrome 1AD

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: 25533962; 25972378; 26168268

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PPP2R5D variants in ClinVar

14 Conditions Cataloged

not providedTotal: 593

Houge-Janssens syndrome 1Total: 64

Inborn genetic diseasesTotal: 51

PPP2R5D-related disorderTotal: 25

not specifiedTotal: 24

Intellectual disabilityTotal: 3

Neurodevelopmental delayTotal: 2

See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006245.4. 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			6 clinvar	134 clinvar	2 clinvar	142
missense	11 clinvar	20 clinvar	260 clinvar	19 clinvar	2 clinvar	312
nonsense	1 clinvar		4 clinvar			5
start loss						0
frameshift			10 clinvar			10
splice donor/acceptor (+/-2bp)			13 clinvar			13
Total	12	20	293	153	4	482

Highest pathogenic variant AF is 0.000002736199

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006245.4	RefSeq	NP_006236.1	16	MANE Select
ENST00000485511.6	Ensembl	ENSP00000417963.1	16	MANE Select
NM_001270476.2	RefSeq	NP_001257405.1	13	Standard
NM_180976.3	RefSeq	NP_851307.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Dopaminergic synapse - Homo sapiens (human)
Oocyte meiosis - Homo sapiens (human)
mRNA surveillance pathway - Homo sapiens (human)
AMPK signaling pathway - Homo sapiens (human)

Biological Process

protein dephosphorylation
signal transduction
nervous system development
negative regulation of peptidyl-threonine phosphorylation
regulation of protein autophosphorylation

Molecular Function

phosphoprotein phosphatase activity
protein serine/threonine phosphatase activity
protein binding
protein phosphatase regulator activity
protein phosphatase activator activity

Cellular Component

protein phosphatase type 2A complex
nucleus
nucleoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000485511
Coding exons: 16
Length: 27844
Individuals with no LoFs: 125720
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125723
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.65	155	346	0.448	0.0000215	3981
Missense (PolyPhen)		35	124.86	0.28031		1535
Synonymous	0.259	131	135	0.972	0.00000800	1141
Loss of Function	5.24	2	35.9	0.0557	0.00000193	408

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)	0.000026	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The B regulatory subunit might modulate substrate selectivity and catalytic activity, and also might direct the localization of the catalytic enzyme to a particular subcellular compartment.;
Disease: DISEASE: Mental retardation, autosomal dominant 35 (MRD35) [MIM:616355]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:25533962, ECO:0000269|PubMed:26168268}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.131

Intolerance Scores

LoFtool: 0.327
RVIS EVS: -0.65
RVIS percentile EVS: 16.36

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.994

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium