Hereditary cerebellar ataxia

Summary

Hereditary cerebellar ataxia (MONDO:0100310) is a disease (an umbrella term covering 5 Mondo subtypes) with 2 cohort genes.

At a glance

• Umbrella term: 5 Mondo subtypes
• Cohort genes: 2
• ClinVar variants: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary cerebellar ataxia
Mondo ID	MONDO:0100310
NCIT	C140268
UMLS	C0270749
MedGen	78726
GARD	0026137
Is cancer (heuristic)	no

Also known as: cerebellar hereditary ataxia · hereditary cerebellar ataxia

Data availability: 2 ClinVar variants · 22 cell lines.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › cerebellar ataxia › hereditary cerebellar ataxia

Subtypes (5): ataxia-pancytopenia syndrome, ataxia telangiectasia, autosomal recessive cerebellar ataxia, X-linked cerebellar ataxia, autosomal dominant cerebellar ataxia

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

2 retrieved; paginated sample, class counts are floors:

2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
871987	NM_001127222.2(CACNA1A):c.2606G>C (p.Arg869Pro)	CACNA1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
3773799	NM_018896.5(CACNA1G):c.4181G>A (p.Arg1394Gln)	CACNA1G	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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
CACNA1G	Orphanet:458803	Spinocerebellar ataxia type 42

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	clinvar
CACNA1G	HGNC:1394	ENSG00000006283	O43497	Voltage-dependent T-type calcium channel subunit alpha-1G	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…
CACNA1G	Voltage-dependent T-type calcium channel subunit alpha-1G	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: 2 · 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	2	111.5×	8e-05

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
CACNA1G	Ion channel	yes		VDCCAlpha1, VDCC_T_a1, 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right hemisphere of cerebellum	2
cerebellar cortex	1
cerebellar hemisphere	1
lateral nuclear group of thalamus	1
right frontal lobe	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
CACNA1G	194	broad	yes	lateral nuclear group of thalamus, right hemisphere of cerebellum, right frontal lobe

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CACNA1G	1,677
CACNA1A	346

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CACNA1A	O00555	4
CACNA1G	O43497	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 2 evidence-associated genes (2 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 2 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	475.8×	0.024	CACNA1A
NCAM signaling for neurite out-growth	1	135.9×	0.024	CACNA1G
Smooth Muscle Contraction	1	132.8×	0.024	CACNA1G
NCAM1 interactions	1	124.1×	0.024	CACNA1G
Regulation of insulin secretion	1	109.8×	0.024	CACNA1A
Integration of energy metabolism	1	87.8×	0.025	CACNA1A
Muscle contraction	1	38.6×	0.042	CACNA1G
Transmission across Chemical Synapses	1	38.1×	0.042	CACNA1A
Axon guidance	1	22.6×	0.054	CACNA1G
Neuronal System	1	22.1×	0.054	CACNA1A
Nervous system development	1	21.5×	0.054	CACNA1G
Developmental Biology	1	7.2×	0.145	CACNA1G
Metabolism	1	5.8×	0.165	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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
calcium ion import across plasma membrane	2	543.6×	7e-05	CACNA1A, CACNA1G
calcium ion transmembrane transport	2	210.7×	2e-04	CACNA1A, CACNA1G
SA node cell to atrial cardiac muscle cell signaling	1	8426.0×	6e-04	CACNA1G
AV node cell to bundle of His cell signaling	1	8426.0×	6e-04	CACNA1G
chemical synaptic transmission	2	77.3×	7e-04	CACNA1A, CACNA1G
response to nickel cation	1	4213.0×	8e-04	CACNA1G
AV node cell action potential	1	2106.5×	0.001	CACNA1G
membrane depolarization during AV node cell action potential	1	1685.2×	0.001	CACNA1G
membrane depolarization during SA node cell action potential	1	1685.2×	0.001	CACNA1G
SA node cell action potential	1	1404.3×	0.001	CACNA1G
sinoatrial node development	1	1053.2×	0.002	CACNA1G
regulation of atrial cardiac muscle cell membrane depolarization	1	936.2×	0.002	CACNA1G
response to amyloid-beta	1	495.6×	0.003	CACNA1A
calcium ion import	1	401.2×	0.004	CACNA1G
cardiac muscle cell action potential involved in contraction	1	351.1×	0.004	CACNA1G
cellular response to amyloid-beta	1	195.9×	0.006	CACNA1A
regulation of heart rate by cardiac conduction	1	187.2×	0.006	CACNA1G
regulation of membrane potential	1	115.4×	0.010	CACNA1G
modulation of chemical synaptic transmission	1	91.6×	0.011	CACNA1A
positive regulation of cytosolic calcium ion concentration	1	58.5×	0.017	CACNA1A

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 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
CACNA1G	NIMODIPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1G	8	4
CACNA1A	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIMODIPINE	4	CACNA1A, CACNA1G
TACRINE	4	CACNA1A, CACNA1G
PIMOZIDE	4	CACNA1G
MIBEFRADIL	4	CACNA1G
SUVECALTAMIDE	2	CACNA1G
FLUNARIZINE	2	CACNA1G
APINOCALTAMIDE	2	CACNA1G
ULIXACALTAMIDE	1	CACNA1G

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CACNA1G	105	Binding:91, Functional:11, ADMET:2, Toxicity:1
CACNA1A	19	Binding:18, Functional:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CACNA1G	105

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

8 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, CACNA1G
TACRINE	4	CACNA1A, CACNA1G
PIMOZIDE	4	CACNA1G
MIBEFRADIL	4	CACNA1G
SUVECALTAMIDE	2	CACNA1G
FLUNARIZINE	2	CACNA1G
APINOCALTAMIDE	2	CACNA1G
ULIXACALTAMIDE	1	CACNA1G

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	CACNA1A, CACNA1G
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: 0.