PIK3R5

Chr 17

phosphoinositide-3-kinase regulatory subunit 5

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

NCBI Gene: 23533 ENSG00000141506 UniProt: Q8WYR1

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.

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]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtAtaxia-oculomotor apraxia 3

Clinical highlights

Gene–disease validity (ClinGen)

Disputed · ataxia with oculomotor apraxia type 3 · AR · ClinGen 2025

evidence questions this relationship

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.39

LOEUF

—

Mechanism

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Background carrier burden — how many people carry a rare variant somewhere in PIK3R5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 53

903 rare PASS variants

Rare truncating (LoF)

1 in 2,100

63 rare PASS variants

Rare synonymous (reference)

1 in 120

470 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PIK3R5. 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 68	1 in 2,100
South Asian	~43k	1 in 62	1 in 1,500
Remaining (unassigned)	~30k	1 in 52	1 in 3,000
European (Finnish)	~27k	1 in 150	1 in 2,900
Admixed American	~22k	1 in 35	1 in 1,700
African / African American	~21k	1 in 73	≈ 1 in 6,000
East Asian	~20k	1 in 74	none seen
Ashkenazi Jewish	~13k	1 in 120	none seen
Middle Eastern	~2,884	1 in 67	none seen

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): All 18 coding exons well covered in gnomAD exomes and genomes.? see exons ↓