Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome

Summary

Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome (MONDO:0011038) is a disease caused by ATP1A3 (GenCC Definitive), with 1 cohort gene and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ATP1A3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 98
• Phenotypes (HPO): 13
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0000648	Optic atrophy	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001284	Areflexia	Very frequent (80-99%)
HP:0001298	Encephalopathy	Very frequent (80-99%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0000496	Abnormality of eye movement	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome
Mondo ID	MONDO:0011038
MeSH	C535351
OMIM	601338
Orphanet	1171
SNOMED CT	720634003
UMLS	C1832466
MedGen	318633
GARD	0001188
Is cancer (heuristic)	no

Also known as: CAPOS · CAPOS syndrome · cerebellar ataxia - areflexia - pes cavus - optic atrophy - sensorineural hearing loss · cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorinural hearing loss · cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss

Data availability: 98 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant optic atrophy › autosomal dominant optic atrophy plus syndrome › cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome

Related subtypes (3): optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy, optic atrophy, hearing loss, and peripheral neuropathy, autosomal dominant, optic atrophy 8

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

98 retrieved; paginated sample, class counts are floors:

35 benign/likely benign, 14 benign, 11 uncertain significance, 8 pathogenic, 8 likely benign, 8 conflicting classifications of pathogenicity, 8 pathogenic/likely pathogenic, 6 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075560	NM_152296.5(ATP1A3):c.1073G>A (p.Gly358Asp)	ATP1A3	Pathogenic	criteria provided, multiple submitters, no conflicts
12915	NM_152296.5(ATP1A3):c.2767G>A (p.Asp923Asn)	ATP1A3	Pathogenic	criteria provided, multiple submitters, no conflicts
156238	NM_152296.5(ATP1A3):c.2452G>A (p.Glu818Lys)	ATP1A3	Pathogenic	criteria provided, multiple submitters, no conflicts
161134	NM_152296.5(ATP1A3):c.2267G>A (p.Arg756His)	ATP1A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1700242	NM_152296.5(ATP1A3):c.2267G>T (p.Arg756Leu)	ATP1A3	Pathogenic	no assertion criteria provided
208704	NM_152296.5(ATP1A3):c.971A>G (p.Glu324Gly)	ATP1A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
216891	NM_152296.5(ATP1A3):c.974G>A (p.Gly325Asp)	ATP1A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218558	NM_152296.5(ATP1A3):c.967C>T (p.Pro323Ser)	ATP1A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
37107	NM_152296.5(ATP1A3):c.2401G>A (p.Asp801Asn)	ATP1A3	Pathogenic	criteria provided, multiple submitters, no conflicts
37108	NM_152296.5(ATP1A3):c.2443G>A (p.Glu815Lys)	ATP1A3	Pathogenic	criteria provided, multiple submitters, no conflicts
37110	NM_152296.5(ATP1A3):c.2839G>A (p.Gly947Arg)	ATP1A3	Pathogenic	criteria provided, multiple submitters, no conflicts
372799	NM_152296.5(ATP1A3):c.2116G>A (p.Gly706Arg)	ATP1A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
425189	NM_152296.5(ATP1A3):c.2266C>T (p.Arg756Cys)	ATP1A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
431156	NM_152296.5(ATP1A3):c.2224G>T (p.Asp742Tyr)	ATP1A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
689735	NM_152296.5(ATP1A3):c.2839G>T (p.Gly947Trp)	ATP1A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
976730	NM_152296.5(ATP1A3):c.2312C>T (p.Thr771Ile)	ATP1A3	Pathogenic	criteria provided, single submitter
1333833	NM_152296.5(ATP1A3):c.2552A>G (p.Gln851Arg)	ATP1A3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1802594	NM_152296.5(ATP1A3):c.265G>T (p.Gly89Cys)	ATP1A3	Likely pathogenic	criteria provided, single submitter
3376411	NM_152296.5(ATP1A3):c.2516T>C (p.Leu839Pro)	ATP1A3	Likely pathogenic	criteria provided, single submitter
3382957	NM_152296.5(ATP1A3):c.2780G>A (p.Cys927Tyr)	ATP1A3	Likely pathogenic	criteria provided, single submitter
431154	NM_152296.5(ATP1A3):c.460A>G (p.Met154Val)	ATP1A3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
807377	NM_152296.5(ATP1A3):c.2543G>C (p.Gly848Ala)	ATP1A3	Likely pathogenic	criteria provided, single submitter
1435191	NM_152296.5(ATP1A3):c.1906G>A (p.Ala636Thr)	ATP1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1686544	NM_152296.5(ATP1A3):c.1549G>C (p.Glu517Gln)	ATP1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
329422	NM_152296.5(ATP1A3):c.994-3C>G	ATP1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
421853	NM_152296.5(ATP1A3):c.2146AAG[1] (p.Lys717del)	ATP1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
429527	NM_152296.5(ATP1A3):c.1765G>T (p.Val589Phe)	ATP1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
468600	NM_152296.5(ATP1A3):c.2653G>A (p.Val885Ile)	ATP1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
625891	NM_152296.5(ATP1A3):c.1192+7G>A	ATP1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
625892	NM_152296.5(ATP1A3):c.1176C>T (p.Thr392=)	ATP1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 4 · 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
ATP1A3	Definitive	Autosomal dominant	cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP1A3	Orphanet:1171	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome
ATP1A3	Orphanet:2131	Alternating hemiplegia of childhood
ATP1A3	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ATP1A3	Orphanet:71517	Rapid-onset dystonia-parkinsonism

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
ATP1A3	HGNC:801	ENSG00000105409	P13637	Sodium/potassium-transporting ATPase subunit alpha-3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP1A3	Sodium/potassium-transporting ATPase subunit alpha-3	This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP1A3	Transcription factor	no		P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_ATPase_IIC

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
cortical plate	1
primary visual cortex	1
superior frontal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP1A3	129	broad	marker	superior frontal gyrus, primary visual cortex, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP1A3	3,876

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP1A3	P13637	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Ion transport by P-type ATPases	1	207.6×	0.023	ATP1A3
Ion homeostasis	1	203.9×	0.023	ATP1A3
Potential therapeutics for SARS	1	114.2×	0.023	ATP1A3
Cardiac conduction	1	108.8×	0.023	ATP1A3
Ion channel transport	1	96.0×	0.023	ATP1A3
Muscle contraction	1	77.2×	0.024	ATP1A3
SARS-CoV Infections	1	55.4×	0.028	ATP1A3
Viral Infection Pathways	1	30.8×	0.044	ATP1A3
Transport of small molecules	1	25.1×	0.044	ATP1A3
Infectious disease	1	24.8×	0.044	ATP1A3
Disease	1	13.1×	0.076	ATP1A3

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
response to glycoside	1	2407.4×	0.002	ATP1A3
cell communication by electrical coupling involved in cardiac conduction	1	1404.3×	0.002	ATP1A3
regulation of resting membrane potential	1	1296.3×	0.002	ATP1A3
neuron projection maintenance	1	1123.5×	0.002	ATP1A3
sodium ion export across plasma membrane	1	1053.2×	0.002	ATP1A3
cellular response to steroid hormone stimulus	1	1053.2×	0.002	ATP1A3
intracellular potassium ion homeostasis	1	991.3×	0.002	ATP1A3
intracellular sodium ion homeostasis	1	766.0×	0.002	ATP1A3
cellular response to amyloid-beta	1	391.9×	0.003	ATP1A3
potassium ion import across plasma membrane	1	366.4×	0.003	ATP1A3
proton transmembrane transport	1	312.1×	0.003	ATP1A3

Therapeutics

Drug target analysis

Approved (phase 4): 1 · 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).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ATP1A3	OMEPRAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP1A3	5	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OMEPRAZOLE	4	ATP1A3
DIGOXIN	4	ATP1A3
DIGITOXIN	4	ATP1A3
LANSOPRAZOLE	4	ATP1A3
ROSTAFUROXIN	2	ATP1A3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ATP1A3	45	Binding:45

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

5 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)
OMEPRAZOLE	4	ATP1A3
DIGOXIN	4	ATP1A3
DIGITOXIN	4	ATP1A3
LANSOPRAZOLE	4	ATP1A3
ROSTAFUROXIN	2	ATP1A3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ATP1A3
B	Phased (≥1) drug, not yet approved	0
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: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT03857607	Not specified	UNKNOWN	Natural History Study of ATP1A3-related Disease