PIK3R2

Chr 19AD

phosphoinositide-3-kinase regulatory subunit 2

Also known as: MPPH, MPPH1, P85B, p85, p85-BETA, p85beta

NCBI Gene: 5296 ENSG00000105647 UniProt: O00459 OMIM: 603157

The protein encoded by PIK3R2 serves as a regulatory subunit of phosphatidylinositol 3-kinase (PI3K), a lipid kinase that phosphorylates phosphatidylinositol to generate second messengers in growth signaling pathways. Gain-of-function mutations cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, inherited in an autosomal dominant pattern.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, Mechanism

Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that phosphorylates phosphatidylinositol and similar compounds, creating second messengers important in growth signaling pathways. PI3K functions as a heterodimer of a regulatory and a catalytic subunit. The protein encoded by this gene is a regulatory component of PI3K. Three transcript variants, one protein coding and the other two non-protein coding, have been found for this gene. [provided by RefSeq, Apr 2019]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1MIM #603387

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes · AD · ClinGen 2021
Definitive · megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 · AD · Illumina
Supportive · megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome · AD · Orphanet

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

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P/LP submissions

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P/LP missense

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LOEUF

GOF

Mechanism· G2P

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GeneReview available — PIK3R2

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

gnomad: Error: gnomAD API error: 400

Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

Background carrier burden — how many people carry a rare variant somewhere in PIK3R2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 70

952 rare PASS variants

Rare truncating (LoF)

1 in 1,900

136 rare PASS variants

Rare synonymous (reference)

1 in 96

503 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PIK3R2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 82	1 in 1,900
South Asian	~43k	1 in 54	1 in 1,400
Remaining (unassigned)	~30k	1 in 57	1 in 820
European (Finnish)	~27k	1 in 260	1 in 2,300
Admixed American	~22k	1 in 79	1 in 1,400
African / African American	~21k	1 in 65	1 in 2,000
East Asian	~20k	1 in 80	1 in 1,400
Ashkenazi Jewish	~13k	1 in 170	≈ 1 in 3,300
Middle Eastern	~2,884	1 in 56	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 13 of 15 coding exons well covered in gnomAD exomes; exon 14 poorly covered; exon 6 marginal. Genomes: all 15.? see exons ↓