PIK3R5

Chr 17AR

phosphoinositide-3-kinase regulatory subunit 5

Also known as: F730038I15Rik, FOAP-2, P101-PI3K, p101

NCBI Gene: 23533 ENSG00000141506 UniProt: Q8WYR1 OMIM: 611317

The PIK3R5 protein is the 101 kD regulatory subunit of phosphoinositide 3-kinase gamma that recruits the catalytic subunit to the plasma membrane through interaction with G protein beta-gamma dimers, enabling G protein-mediated signaling pathways involved in cell growth and survival. Mutations cause ataxia-oculomotor apraxia 3, which follows autosomal recessive inheritance and primarily affects cerebellar and oculomotor systems. The gene is highly constrained against loss-of-function variation (LOEUF 0.391), indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Phosphatidylinositol 3-kinases (PI3Ks) phosphorylate the inositol ring of phosphatidylinositol at the 3-prime position, and play important roles in cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. The PI3Ks are divided into three classes: I, II and III, and only the class I PI3Ks are involved in oncogenesis. This gene encodes the 101 kD regulatory subunit of the class I PI3K gamma complex, which is a dimeric enzyme, consisting of a 110 kD catalytic subunit gamma and a regulatory subunit of either 55, 87 or 101 kD. This protein recruits the catalytic subunit from the cytosol to the plasma membrane through high-affinity interaction with G-beta-gamma proteins. Multiple alternatively spliced transcript variants encoding two distinct isoforms have been found. [provided by RefSeq, Oct 2011]

OMIM ResearchGenerating clinical summary…

ARLOEUF 0.391 OMIM phenotype

Clinical Summary— PIK3R5

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Gene-Disease Validity (ClinGen)

ataxia with oculomotor apraxia type 3 · ARDisputed

Disputed — evidence questions this relationship

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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ClinVar Variants

122 VUS of 202 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.39LOEUF

pLI 0.300

Z-score 4.70

OE 0.23 (0.14–0.39)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.86Z-score

OE missense 0.65 (0.60–0.71)

352 obs / 538.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.23 (0.14–0.39)

0≤0.351.4

Missense OE?0.65 (0.60–0.71)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 10 / 43.4Missense obs/exp: 352 / 538.8Syn Z: 1.49

ClinVar Variant Classifications

202 submitted variants in ClinVar

ClinVar

Classification Summary

VUS122

Likely Benign24

Benign18

Conflicting4

122

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	120	2	0	122
Likely Benign	0	6	2	16	24
Benign	0	2	7	9	18
Conflicting	—				4
Total	0	128	11	25	168

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap PIK3R5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →