Spinocerebellar ataxia type 6

Summary

Spinocerebellar ataxia type 6 (MONDO:0008457) is a disease caused by CACNA1A (GenCC Strong), with 1 cohort gene and 12 clinical trials. Top therapeutic interventions include levacetylleucine, troriluzole, and rimtuzalcap.

At a glance

• Prevalence: 1-9 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CACNA1A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 175
• Phenotypes (HPO): 19
• Clinical trials: 12

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Worldwide	Validated
Point prevalence	1-9 / 100 000	1.7	Japan	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0000639	Nystagmus	Very frequent (80-99%)
HP:0002066	Gait ataxia	Very frequent (80-99%)
HP:0002073	Progressive cerebellar ataxia	Very frequent (80-99%)
HP:0002080	Intention tremor	Very frequent (80-99%)
HP:0002172	Postural instability	Very frequent (80-99%)
HP:0002311	Incoordination	Very frequent (80-99%)
HP:0002317	Unsteady gait	Very frequent (80-99%)
HP:0007979	Gaze-evoked horizontal nystagmus	Very frequent (80-99%)
HP:0030511	Bradyopsia	Very frequent (80-99%)
HP:0000504	Abnormality of vision	Frequent (30-79%)
HP:0000651	Diplopia	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0010544	Vertical nystagmus	Frequent (30-79%)
HP:0030842	Choking episodes	Frequent (30-79%)
HP:0000643	Blepharospasm	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia type 6
Mondo ID	MONDO:0008457
OMIM	183086
Orphanet	98758
DOID	DOID:0050956
ICD-11	1056119281
NCIT	C142838
SNOMED CT	715752006
UMLS	C0752124
MedGen	148458
GARD	0010351
Is cancer (heuristic)	no

Also known as: autosomal dominant cerebellar ataxia type III caused by mutation in CACNA1A · CACNA1A autosomal dominant cerebellar ataxia type III · SCA6 · spinocerebellar ataxia 6 · spinocerebellar ataxia type 6

Data availability: 175 ClinVar variants · 4 GenCC gene-disease records · 10 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 dominant disease › autosomal dominant cerebellar ataxia › autosomal dominant cerebellar ataxia type III › spinocerebellar ataxia type 6

Related subtypes (9): spinocerebellar ataxia type 31, spinocerebellar ataxia type 5, spinocerebellar ataxia type 11, spinocerebellar ataxia type 26, spinocerebellar ataxia type 30, spinocerebellar ataxia type 38, spinocerebellar ataxia type 41, spinocerebellar ataxia type 42, spinocerebellar ataxia 45

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

175 retrieved; paginated sample, class counts are floors:

34 conflicting classifications of pathogenicity, 34 uncertain significance, 24 pathogenic/likely pathogenic, 21 pathogenic, 21 benign, 18 likely pathogenic, 16 benign/likely benign, 5 not provided, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027687	NM_001127222.2(CACNA1A):c.826G>T (p.Glu276Ter)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1298310	NM_001127222.2(CACNA1A):c.3414del (p.Thr1139fs)	CACNA1A	Pathogenic	no assertion criteria provided
1338921	NM_001127222.2(CACNA1A):c.5335C>T (p.Arg1779Ter)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1398258	NM_001127222.2(CACNA1A):c.841del (p.Cys281fs)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1421109	NM_001127222.2(CACNA1A):c.5422G>A (p.Val1808Ile)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1441063	NM_001127222.2(CACNA1A):c.2311A>T (p.Lys771Ter)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1679523	NM_001127222.2(CACNA1A):c.4519G>A (p.Ala1507Thr)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1679524	NM_001127222.2(CACNA1A):c.4031T>C (p.Leu1344Pro)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679527	NM_001127222.2(CACNA1A):c.2137G>A (p.Val713Met)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1679533	NM_001127222.2(CACNA1A):c.5015dup (p.Gln1673fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1809801	NM_001127222.2(CACNA1A):c.1805T>G (p.Leu602Arg)	CACNA1A	Pathogenic	no assertion criteria provided
195935	NM_001127222.2(CACNA1A):c.4174G>A (p.Val1392Met)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
216896	NM_001127222.2(CACNA1A):c.904G>A (p.Asp302Asn)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2502284	NM_001127222.2(CACNA1A):c.1237C>T (p.Gln413Ter)	CACNA1A	Pathogenic	criteria provided, single submitter
254268	NM_001127222.2(CACNA1A):c.2134G>A (p.Ala712Thr)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279951	NM_001127222.2(CACNA1A):c.4494CTT[2] (p.Phe1501del)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
3383352	NM_001127222.2(CACNA1A):c.1972dup (p.Met658fs)	CACNA1A	Pathogenic	criteria provided, single submitter
380972	NM_001127222.2(CACNA1A):c.4043G>A (p.Arg1348Gln)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
420055	NM_001127222.2(CACNA1A):c.5393C>T (p.Ser1798Leu)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
420945	NM_001127222.2(CACNA1A):c.4055C>T (p.Pro1352Leu)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
422063	NM_001127222.2(CACNA1A):c.4927G>A (p.Asp1643Asn)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
422557	NM_001127222.2(CACNA1A):c.1984C>T (p.Gln662Ter)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
449943	NM_001127222.2(CACNA1A):c.4897G>A (p.Asp1633Asn)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
450171	NM_001127222.2(CACNA1A):c.2133C>G (p.Ile711Met)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
451238	NM_001127222.2(CACNA1A):c.2958_2959dup (p.Arg987fs)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
453193	NM_001127222.2(CACNA1A):c.6397C>T (p.Arg2133Ter)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
476244	NM_001127222.2(CACNA1A):c.2904_2929del (p.Pro969fs)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
523785	NM_001127222.2(CACNA1A):c.4987C>T (p.Arg1663Ter)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
545691	NM_001127222.2(CACNA1A):c.835C>T (p.Arg279Cys)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
562099	NM_001127222.2(CACNA1A):c.6937CAG[(21_30)]	CACNA1A	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 7 · 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
CACNA1A	Definitive	Autosomal dominant	episodic ataxia type 2	23

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CACNA1A	Orphanet:2131	Alternating hemiplegia of childhood
CACNA1A	Orphanet:2382	Lennox-Gastaut syndrome
CACNA1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CACNA1A	Orphanet:569	Familial or sporadic hemiplegic migraine
CACNA1A	Orphanet:71518	Benign paroxysmal torticollis of infancy
CACNA1A	Orphanet:97	Familial paroxysmal ataxia
CACNA1A	Orphanet:98758	Spinocerebellar ataxia type 6

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
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CACNA1A	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Ion channel	1	111.5×	0.009

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom

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 cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CACNA1A	346

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CACNA1A	O00555	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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×	0.006	CACNA1A
Regulation of insulin secretion	1	219.6×	0.011	CACNA1A
Integration of energy metabolism	1	175.7×	0.011	CACNA1A
Transmission across Chemical Synapses	1	76.1×	0.020	CACNA1A
Neuronal System	1	44.3×	0.027	CACNA1A
Metabolism	1	11.6×	0.086	CACNA1A

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 amyloid-beta	1	991.3×	0.006	CACNA1A
calcium ion import across plasma membrane	1	543.6×	0.006	CACNA1A
cellular response to amyloid-beta	1	391.9×	0.006	CACNA1A
calcium ion transmembrane transport	1	210.7×	0.008	CACNA1A
modulation of chemical synaptic transmission	1	183.2×	0.008	CACNA1A
positive regulation of cytosolic calcium ion concentration	1	117.0×	0.010	CACNA1A
chemical synaptic transmission	1	77.3×	0.013	CACNA1A

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
CACNA1A	NIMODIPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1A	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIMODIPINE	4	CACNA1A
TACRINE	4	CACNA1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CACNA1A	19	Binding:18, Functional:1

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	CACNA1A
TACRINE	4	CACNA1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CACNA1A
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: 12.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	7
PHASE3	3
PHASE2	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT07221292	PHASE3	NOT_YET_RECRUITING	Pivotal Study of N-acetyl-L-leucine for CACNA1A
NCT03378414	PHASE2	NOT_YET_RECRUITING	Umbilical Cord Mesenchymal Stem Cells Therapy (19#iSCLife®-SA) for Patients With Spinocerebellar Ataxia
NCT04301284	PHASE2	WITHDRAWN	Study of CAD-1883 for Spinocerebellar Ataxia
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT05826171	Not specified	ACTIVE_NOT_RECRUITING	Priming Motor Learning Through Exercise in People With Spinocerebellar Ataxia
NCT07288437	Not specified	RECRUITING	Deep Brain Stimulation for Spinocerebellar Ataxia
NCT07325487	Not specified	NOT_YET_RECRUITING	Interposed Nucleus aDBS for Ataxia
NCT01060371	Not specified	UNKNOWN	Natural History Study of and Genetic Modifiers in Spinocerebellar Ataxias
NCT01934998	Not specified	COMPLETED	Parkinsonism in Spinocerebellar Ataxia Type 6
NCT04268147	Not specified	COMPLETED	Instrumented Data Exchange for Ataxia Study

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LEVACETYLLEUCINE	4	1
TRORILUZOLE	3	3
RIMTUZALCAP	2	1