PPP2R1A

protein-coding

protein phosphatase 2 scaffold subunit Aalpha, the group of Protein phosphatase 2 scaffold subunits|STRIPAK complex|Armadillo like helical domain containing|MicroRNA protein coding host genes

Gene summary

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]

MANE transcript

NM_014225.6

Inheritance

ClinVar variants

P:30U:228B:229

Top phenotype

Houge-Janssens syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr19:52,170,936-52,229,518

External References & Databases

Ensembl (ENSG00000105568)

Transcript & Mutation Effects

hg38 • Region Span ~58.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Houge-Janssens syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014605

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: PanelApp Australia

Houge-Janssens syndrome 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014605

Submitter: G2P

Houge-Janssens syndrome 2SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014605

Submitter: Orphanet

Houge-Janssens syndrome 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014605

Submitter: Illumina

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*PPP2R1A* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2015 (PMIDs: 25533962, 26168268). Individuals with *PPP2R1A* pathogenic variants present with developmental delay, intellectual disability, hypotonia, and language delay (PMIDs: 26168268, 33106617). Other common features include hypermobile joints, behavioral problems, epilepsy, and macrocephaly (PMIDs: 26168268, 33106617). Over 30 individuals with neurodevelopmental disorders and a *de novo* PPP2R1A missense variant have been reported in the literature (PMIDs: 26168268, 31531803, 31687265, 33106617). Only 10 probands are included in this curation because the maximum score for genetic evidence (12 points) has been reached. *PPP2R1A* encodes the scaffolding Aα subunit of protein phosphatase type 2A (PP2A). The Aα subunit acts as a scaffolding molecule, coordinating the assembly of the catalytic C subunit and a variable regulatory B subunit to produce functionally diverse PP2A heterotrimers (PMID: 9989501). *PPP2R1A* variants cluster in the HEAT repeat and intrarepeat region of the protein (PMID: 33106617). The reported *de novo* recurrent and clustered missense variants that reduce catalytic C subunit binding, as well as variants that decrease PP2A activity but not catalytic subunit binding, suggest that *PPP2R1A* variants cause PP2A dysfunctions via both dominant-negative and haploinsufficiency mechanisms (PMIDs: 26168268, 33106617). The gene-disease relationship is also supported by experimental evidence, including protein interaction and biochemical function (PMIDs: 26168268, 33106617). In summary, there is definitive evidence supporting the relationship between *PPP2R1A* 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 classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 16, 2022 (SOP Version 9).

Clinical Genomic Database (CGD)

Houge-Janssens syndrome 2AD

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; 26168268

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PPP2R1A variants in ClinVar

13 Conditions Cataloged

not providedTotal: 576

Houge-Janssens syndrome 2Total: 46

not specifiedTotal: 41

Inborn genetic diseasesTotal: 33

PPP2R1A-related disorderTotal: 17

See casesTotal: 3

Intellectual disabilityTotal: 2

Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014225.6. 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			10 clinvar	182 clinvar	3 clinvar	195
missense	4 clinvar	25 clinvar	206 clinvar	29 clinvar	15 clinvar	279
nonsense			4 clinvar			4
start loss						0
frameshift	1 clinvar		2 clinvar			3
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	5	25	228	211	18	487

Highest pathogenic variant AF is 0.000004788931

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 60 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014225.6	RefSeq	NP_055040.2	15	MANE Select
ENST00000322088.11	Ensembl	ENSP00000324804.6	15	MANE Select
NM_001363656.2	RefSeq	NP_001350585.1	11	Standard
ENST00000391791.4	Ensembl	ENSP00000375668.4	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
TGF-beta signaling pathway - Homo sapiens (human)
Dopaminergic synapse - Homo sapiens (human)
Oocyte meiosis - Homo sapiens (human)
Long-term depression - Homo sapiens (human)

Biological Process

G2/M transition of mitotic cell cycle
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
inactivation of MAPK activity
regulation of DNA replication
regulation of transcription, DNA-templated

Molecular Function

protein serine/threonine phosphatase activity
protein binding
protein phosphatase regulator activity
protein heterodimerization activity
protein antigen binding

Cellular Component

protein phosphatase type 2A complex
chromosome, centromeric region
nucleus
cytoplasm
mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000322088
Coding exons: 15
Length: 37396
Individuals with no LoFs: 125741
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125748
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.46	123	361	0.340	0.0000219	3790
Missense (PolyPhen)		17	92.642	0.1835		849
Synonymous	0.553	150	159	0.944	0.0000101	1231
Loss of Function	4.42	4	30.2	0.133	0.00000152	334

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)	0.000062	0.000062	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The PR65 subunit of protein phosphatase 2A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit. Upon interaction with GNA12 promotes dephosphorylation of microtubule associated protein TAU/MAPT (PubMed:15525651). Required for proper chromosome segregation and for centromeric localization of SGO1 in mitosis (PubMed:16580887). {ECO:0000269|PubMed:15525651, ECO:0000269|PubMed:16580887}.;
Disease: DISEASE: Mental retardation, autosomal dominant 36 (MRD36) [MIM:616362]: 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: 0.281

Intolerance Scores

LoFtool: 0.411
RVIS EVS: -0.18
RVIS percentile EVS: 39.95

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.992

Gene Damage Prediction

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