Ataxia with oculomotor apraxia type 3

Summary

Ataxia with oculomotor apraxia type 3 (MONDO:0014084) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ataxia with oculomotor apraxia type 3
Mondo ID	MONDO:0014084
OMIM	615217
DOID	DOID:0060557
UMLS	C3554690
MedGen	767604
GARD	0013112
Is cancer (heuristic)	no

Also known as: AOA3 · ataxia-oculomotor apraxia 3 · ataxia-oculomotor apraxia type 3 · ataxia-oculomotor apraxia-3

Data availability: 21 ClinVar variants · 2 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive cerebellar ataxia › ataxia with oculomotor apraxia type 3

Related subtypes (28): Charlevoix-Saguenay spastic ataxia, infantile-onset autosomal recessive nonprogressive cerebellar ataxia, autosomal recessive spinocerebellar ataxia 7, autosomal recessive ataxia, Beauce type, RIDDLE syndrome, autosomal recessive ataxia due to ubiquinone deficiency, autosomal recessive spinocerebellar ataxia 10, autosomal recessive spinocerebellar ataxia 14, autosomal recessive spinocerebellar ataxia 16, Lichtenstein-Knorr syndrome, autosomal recessive spinocerebellar ataxia 20, spinocerebellar ataxia, autosomal recessive 22, spinocerebellar ataxia, autosomal recessive 24, autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome, autosomal recessive congenital cerebellar ataxia, autosomal recessive metabolic cerebellar ataxia, autosomal recessive degenerative and progressive cerebellar ataxia, autosomal recessive syndromic cerebellar ataxia, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy, spinocerebellar ataxia, autosomal recessive 29, spinocerebellar ataxia, autosomal recessive 30, spinocerebellar ataxia, autosomal recessive 31, spinocerebellar ataxia, autosomal recessive 27, spinocerebellar ataxia, autosomal recessive 28, spinocerebellar ataxia, autosomal recessive 25, spinocerebellar ataxia, autosomal recessive 26, spinocerebellar ataxia, autosomal recessive 32, spinocerebellar ataxia, autosomal recessive 33

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

21 retrieved; paginated sample, class counts are floors:

11 benign, 7 uncertain significance, 2 conflicting classifications of pathogenicity, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
211906	NM_001142633.3(PIK3R5):c.2557C>T (p.Pro853Ser)	PIK3R5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
48651	NM_001142633.3(PIK3R5):c.1885C>T (p.Pro629Ser)	PIK3R5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030201	NM_001142633.3(PIK3R5):c.2425G>A (p.Gly809Ser)	PIK3R5	Uncertain significance	criteria provided, single submitter
1031877	NM_001142633.3(PIK3R5):c.1207C>T (p.Pro403Ser)	PIK3R5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032660	NM_001142633.3(PIK3R5):c.470G>A (p.Arg157His)	PIK3R5	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434862	NM_001142633.3(PIK3R5):c.2354A>G (p.Asn785Ser)	PIK3R5	Uncertain significance	criteria provided, single submitter
2434863	NM_001142633.3(PIK3R5):c.2555C>T (p.Thr852Met)	PIK3R5	Uncertain significance	criteria provided, single submitter
2434864	NM_001142633.3(PIK3R5):c.2338GTG[1] (p.Val781del)	PIK3R5	Uncertain significance	criteria provided, single submitter
2442065	NM_001142633.3(PIK3R5):c.1634G>A (p.Arg545His)	PIK3R5	Uncertain significance	criteria provided, single submitter
129892	NM_001142633.3(PIK3R5):c.1011C>T (p.Asp337=)	PIK3R5	Benign	criteria provided, multiple submitters, no conflicts
129893	NM_001142633.3(PIK3R5):c.1075T>C (p.Leu359=)	PIK3R5	Benign	criteria provided, multiple submitters, no conflicts
129894	NM_001142633.3(PIK3R5):c.837C>T (p.His279=)	PIK3R5	Benign	criteria provided, multiple submitters, no conflicts
129895	NM_001142633.3(PIK3R5):c.933A>G (p.Leu311=)	PIK3R5	Benign	criteria provided, multiple submitters, no conflicts
130136	NM_001142633.3(PIK3R5):c.1101G>A (p.Ser367=)	PIK3R5	Benign	criteria provided, multiple submitters, no conflicts
1327032	NM_001142633.3(PIK3R5):c.2496-46A>G	PIK3R5	Benign	criteria provided, multiple submitters, no conflicts
1327033	NM_001142633.3(PIK3R5):c.2383-27T>C	PIK3R5	Benign	criteria provided, multiple submitters, no conflicts
1327034	NM_001142633.3(PIK3R5):c.657+41T>C	PIK3R5	Benign	criteria provided, multiple submitters, no conflicts
1327035	NM_001142633.3(PIK3R5):c.205-21C>T	PIK3R5	Benign	criteria provided, multiple submitters, no conflicts
257556	NM_001142633.3(PIK3R5):c.2299+13G>A	PIK3R5	Benign	criteria provided, multiple submitters, no conflicts
257557	NM_001142633.3(PIK3R5):c.2299+18T>G	PIK3R5	Benign	criteria provided, multiple submitters, no conflicts
2505073	NM_001142633.3(PIK3R5):c.13G>A (p.Ala5Thr)	PIK3R5	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PIK3R5	Supportive	Autosomal recessive	spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PIK3R5	Orphanet:64753	Spinocerebellar ataxia with axonal neuropathy type 2

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PIK3R5	HGNC:30035	ENSG00000141506	Q8WYR1	Phosphoinositide 3-kinase regulatory subunit 5	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PIK3R5	Phosphoinositide 3-kinase regulatory subunit 5	Regulatory subunit of the PI3K gamma complex.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIK3R5	Other/Unknown	no		PIK3R5/6

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
granulocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIK3R5	193	broad	marker	granulocyte, blood, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIK3R5	1,380

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PIK3R5	Q8WYR1	71.39

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Co-stimulation by ICOS	1	1038.2×	0.005	PIK3R5
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	1	951.7×	0.005	PIK3R5
G beta:gamma signalling through PI3Kgamma	1	439.2×	0.006	PIK3R5
CD28 dependent PI3K/Akt signaling	1	393.8×	0.006	PIK3R5
GPVI-mediated activation cascade	1	308.6×	0.006	PIK3R5
Synthesis of PIPs at the plasma membrane	1	211.5×	0.007	PIK3R5
Constitutive Signaling by Aberrant PI3K in Cancer	1	126.9×	0.010	PIK3R5
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	96.8×	0.012	PIK3R5
PIP3 activates AKT signaling	1	66.8×	0.015	PIK3R5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
phosphatidylinositol metabolic process	1	887.0×	0.005	PIK3R5
positive regulation of MAP kinase activity	1	648.1×	0.005	PIK3R5
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	210.7×	0.009	PIK3R5
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	78.4×	0.019	PIK3R5
immune response	1	47.1×	0.025	PIK3R5
G protein-coupled receptor signaling pathway	1	36.2×	0.028	PIK3R5

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIK3R5	4	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DACTOLISIB	3	PIK3R5
BUPARLISIB	3	PIK3R5
PICTILISIB	2	PIK3R5
ROGINOLISIB	2	PIK3R5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PIK3R5	8	Binding:8

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

4 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
DACTOLISIB	3	PIK3R5
BUPARLISIB	3	PIK3R5
PICTILISIB	2	PIK3R5
ROGINOLISIB	2	PIK3R5

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	PIK3R5
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.