Episodic ataxia type 5

Summary

Episodic ataxia type 5 (MONDO:0013464) is a disease with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 133
• Phenotypes (HPO): 6
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

6 HPO clinical features (Orphanet curated; top 6 by frequency):

HPO ID	Term	Frequency
HP:0000640	Gaze-evoked nystagmus	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0002078	Truncal ataxia	Frequent (30-79%)
HP:0002172	Postural instability	Frequent (30-79%)
HP:0002321	Vertigo	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	episodic ataxia type 5
Mondo ID	MONDO:0013464
MeSH	C566601
OMIM	613855
Orphanet	211067
DOID	DOID:0050993
SNOMED CT	718756005
UMLS	C1866039
MedGen	356142
GARD	0017113
Is cancer (heuristic)	no

Also known as: CACNB4 hereditary episodic ataxia · EA5 · episodic ataxia, type 5 · hereditary episodic ataxia caused by mutation in CACNB4

Data availability: 133 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › atactic disorder › hereditary ataxia › hereditary episodic ataxia › episodic ataxia type 5

Related subtypes (8): episodic ataxia type 2, episodic ataxia type 1, episodic ataxia type 4, episodic ataxia type 3, episodic ataxia type 7, episodic ataxia type 6, episodic ataxia type 8, episodic ataxia, type 9

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

133 retrieved; paginated sample, class counts are floors:

70 uncertain significance, 40 benign, 12 conflicting classifications of pathogenicity, 9 benign/likely benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
204935	NM_000726.5(CACNB4):c.1355G>A (p.Arg452Lys)	CACNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204938	NM_000726.5(CACNB4):c.8C>T (p.Ser3Phe)	CACNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204939	NM_000726.5(CACNB4):c.44C>G (p.Pro15Arg)	CACNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331562	NM_000726.5(CACNB4):c.*5022A>G	CACNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331590	NM_000726.5(CACNB4):c.*2188T>G	CACNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331618	NM_000726.5(CACNB4):c.*737C>T	CACNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331620	NM_000726.5(CACNB4):c.*624A>T	CACNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
446974	NM_000726.5(CACNB4):c.91A>C (p.Ser31Arg)	CACNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
567325	NM_000726.5(CACNB4):c.1310G>A (p.Arg437Gln)	CACNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
7608	NM_000726.5(CACNB4):c.311G>T (p.Cys104Phe)	CACNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
842227	NM_000726.5(CACNB4):c.40G>C (p.Gly14Arg)	CACNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193120	NM_000726.5(CACNB4):c.5C>T (p.Ser2Phe)	LOC129934925	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2688709	NM_000726.5(CACNB4):c.164A>G (p.Tyr55Cys)	CACNB4	Uncertain significance	criteria provided, single submitter
331547	NM_000726.5(CACNB4):c.*6183A>G	CACNB4	Uncertain significance	criteria provided, single submitter
331550	NM_000726.5(CACNB4):c.*5977G>T	CACNB4	Uncertain significance	criteria provided, single submitter
331551	NM_000726.5(CACNB4):c.*5863T>G	CACNB4	Uncertain significance	criteria provided, single submitter
331555	NM_000726.5(CACNB4):c.*5487T>C	CACNB4	Uncertain significance	criteria provided, single submitter
331556	NM_000726.5(CACNB4):c.*5433A>G	CACNB4	Uncertain significance	criteria provided, single submitter
331557	NM_000726.5(CACNB4):c.*5418T>C	CACNB4	Uncertain significance	criteria provided, single submitter
331565	NM_000726.5(CACNB4):c.*4919G>A	CACNB4	Uncertain significance	criteria provided, single submitter
331566	NM_000726.5(CACNB4):c.*4845T>C	CACNB4	Uncertain significance	criteria provided, single submitter
331570	NM_000726.5(CACNB4):c.*4569A>G	CACNB4	Uncertain significance	criteria provided, single submitter
331571	NM_000726.5(CACNB4):c.*4145T>C	CACNB4	Uncertain significance	criteria provided, single submitter
331572	NM_000726.5(CACNB4):c.*4131A>G	CACNB4	Uncertain significance	criteria provided, single submitter
331575	NM_000726.5(CACNB4):c.*3688G>A	CACNB4	Uncertain significance	criteria provided, single submitter
331576	NM_000726.5(CACNB4):c.*3668T>C	CACNB4	Uncertain significance	criteria provided, single submitter
331577	NM_000726.5(CACNB4):c.*3475A>T	CACNB4	Uncertain significance	criteria provided, single submitter
331578	NM_000726.5(CACNB4):c.*3387C>G	CACNB4	Uncertain significance	criteria provided, single submitter
331580	NM_000726.5(CACNB4):c.*2924T>C	CACNB4	Uncertain significance	criteria provided, single submitter
331586	NM_000726.5(CACNB4):c.*2542G>A	CACNB4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
CACNB4	Supportive	Autosomal dominant	episodic ataxia type 5	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CACNB4	Orphanet:211067	Episodic ataxia type 5
CACNB4	Orphanet:307	Juvenile myoclonic epilepsy

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
CACNB4	HGNC:1404	ENSG00000182389	O00305	Voltage-dependent L-type calcium channel subunit beta-4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CACNB4	Voltage-dependent L-type calcium channel subunit beta-4	The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition…

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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CACNB4	Scaffold/PPI	no		VDCC_L_bsu, SH3_domain, GK/Ca_channel_bsu

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
cerebellar vermis	1
lateral nuclear group of thalamus	1
primary visual cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CACNB4	201	broad	marker	cerebellar vermis, lateral nuclear group of thalamus, primary visual cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CACNB4	1,366

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CACNB4	O00305	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Presynaptic depolarization and calcium channel opening	1	951.7×	0.008	CACNB4
NCAM signaling for neurite out-growth	1	271.9×	0.011	CACNB4
NCAM1 interactions	1	248.3×	0.011	CACNB4
Transmission across Chemical Synapses	1	76.1×	0.026	CACNB4
Axon guidance	1	45.1×	0.027	CACNB4
Neuronal System	1	44.3×	0.027	CACNB4
Nervous system development	1	42.9×	0.027	CACNB4
Developmental Biology	1	14.5×	0.069	CACNB4

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
gamma-aminobutyric acid secretion	1	4213.0×	0.002	CACNB4
cAMP metabolic process	1	4213.0×	0.002	CACNB4
positive regulation of protein localization to nucleolus	1	2808.7×	0.002	CACNB4
Peyer’s patch development	1	2106.5×	0.002	CACNB4
neuronal action potential propagation	1	1404.3×	0.003	CACNB4
muscle cell development	1	936.2×	0.004	CACNB4
detection of light stimulus involved in visual perception	1	648.1×	0.004	CACNB4
gamma-aminobutyric acid signaling pathway	1	543.6×	0.004	CACNB4
neuromuscular junction development	1	526.6×	0.004	CACNB4
adult walking behavior	1	495.6×	0.004	CACNB4
regulation of synaptic vesicle exocytosis	1	455.5×	0.004	CACNB4
spleen development	1	401.2×	0.004	CACNB4
synaptic transmission, glutamatergic	1	358.6×	0.004	CACNB4
negative regulation of G1/S transition of mitotic cell cycle	1	358.6×	0.004	CACNB4
thymus development	1	337.0×	0.004	CACNB4
calcium ion transmembrane transport	1	210.7×	0.006	CACNB4
calcium ion transport	1	181.2×	0.007	CACNB4
cellular response to leukemia inhibitory factor	1	159.0×	0.007	CACNB4
T cell receptor signaling pathway	1	151.8×	0.007	CACNB4
chemical synaptic transmission	1	77.3×	0.014	CACNB4
negative regulation of cell population proliferation	1	42.1×	0.024	CACNB4

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
CACNB4	NIMODIPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNB4	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIMODIPINE	4	CACNB4
TACRINE	4	CACNB4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CACNB4	13	Binding:13

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

2 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)
NIMODIPINE	4	CACNB4
TACRINE	4	CACNB4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CACNB4
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: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

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