PIK3R5

protein-coding

phosphoinositide-3-kinase regulatory subunit 5

Gene summary

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]

MANE transcript

NM_001142633.3

Inheritance

ClinVar variants

U:135B:37

Top phenotype

Ataxia-oculomotor apraxia 3

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chr17:8,878,911-8,965,712

External References & Databases

Ensembl (ENSG00000141506)

Transcript & Mutation Effects

hg38 • Region Span ~86.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ataxia with oculomotor apraxia type 3LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014084

Submitter: PanelApp Australia

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018996

Submitter: Orphanet

ataxia with oculomotor apraxia type 3NO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0014084

Submitter: ClinGen

*PIK3R5* was first reported in relation to autosomal recessive ataxia-oculomotor apraxia in 2012 in a consanguineous family of which four siblings harbored the same homozygous variant in *PIK3R5* (c.1885C>T, p.P629S) and were affected by ataxia, oculomotor apraxia, sensory axonal neuropathy, progressive distal muscular atrophy, and cerebellar atrophy (Al Tassan *et al.*, PMID: 22065524). However, this variant has a total minor allele frequency of 0.001525 in the general population, is particularly common among the African/African American alleles, with a Grpmax Filtering Allele Frequency of 0.02622, and is observed in thirty homozygotes (Genome Aggregation Database v4.1). To date, no additional *PIK3R5* variants have been reported in relation to autosomal recessive ataxia-oculomotor apraxia. Additional human cases of *PIK3R5*-related ataxia have not been found in the literature. A recent cohort study of 52 patients affected by autosomal recessive cerebellar ataxia with oculomotor apraxia did not detect any variants in *PIK3R5* (PMID: 35426160). This gene-disease relationship is supported by expression studies by Al Tassan *et al.* who demonstrated ubiquitous expression of the PIK3R5 gene in human tissues with high expression in the brain (PMID: 22065524). To date, no publications in scientific literature can be found indicating protein function studies or non-human models showing the ocular motility or coordination and movement deficient phenotype observed in human patients with ataxia-oculomotor apraxia. In summary, the evidence supporting the relationship between *PIK3R5* and autosomal recessive ataxia-oculomotor apraxia has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *PIK3R5* plays in this disease. This classification was approved by the ClinGen Cerebellar Ataxia GCEP on the meeting date April 9, 2025 (SOP Version 11).

Clinical Genomic Database (CGD)

Ataxia-oculomotor apraxia 3AR

Manifestation: 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: 22065524

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PIK3R5 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 131

not providedTotal: 30

Ataxia with oculomotor apraxia type 3Total: 10

PIK3R5-related disorderTotal: 9

Spastic ataxiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001142633.3. 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			5 clinvar	21 clinvar	4 clinvar	30
missense			127 clinvar	10 clinvar	2 clinvar	139
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	135	31	6	172

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 30 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001142633.3	RefSeq	NP_001136105.1	18	MANE Select
ENST00000447110.6	Ensembl	ENSP00000392812.1	18	MANE Select
NM_001251851.2	RefSeq	NP_001238780.1	10	Standard
NM_001251852.2	RefSeq	NP_001238781.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Platelet activation - Homo sapiens (human)
Oxytocin signaling pathway - Homo sapiens (human)
Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
Adrenergic signaling in cardiomyocytes - Homo sapiens (human)

Biological Process

G protein-coupled receptor signaling pathway
phosphatidylinositol 3-kinase signaling
positive regulation of phosphatidylinositol 3-kinase signaling
platelet activation
positive regulation of MAP kinase activity

Molecular Function

G-protein beta/gamma-subunit complex binding
phosphatidylinositol-4,5-bisphosphate 3-kinase activity
1-phosphatidylinositol-3-kinase regulator activity

Cellular Component

nucleus
cytoplasm
microtubule organizing center
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000447110
Coding exons: 18
Length: 86797
Individuals with no LoFs: 125726
Homozygous LoFs: 0
Heterozygous LoFs: 22
Defined: 125748
p: 0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.86	352	539	0.653	0.0000336	5626
Missense (PolyPhen)		74	170.8	0.43326		1755
Synonymous	1.49	202	231	0.875	0.0000142	1851
Loss of Function	4.70	10	43.4	0.231	0.00000216	473

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000049	0.000046	rare
European (Non-Finnish)	0.00010	0.000097	rare
South Asian	0.00014	0.00013	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulatory subunit of the PI3K gamma complex. Required for recruitment of the catalytic subunit to the plasma membrane via interaction with beta-gamma G protein dimers. Required for G protein-mediated activation of PIK3CG (By similarity). {ECO:0000250}.;
Disease: DISEASE: Ataxia-oculomotor apraxia 3 (AOA3) [MIM:615217]: An autosomal recessive disease characterized by cerebellar ataxia, oculomotor apraxia, areflexia and peripheral neuropathy. {ECO:0000269|PubMed:22065524}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.101

Intolerance Scores

LoFtool: 0.227
RVIS EVS: -0.46
RVIS percentile EVS: 23.66

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.503

Gene Damage Prediction

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