Spinocerebellar ataxia type 42

Summary

Spinocerebellar ataxia type 42 (MONDO:0014776) is a disease caused by CACNA1G (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CACNA1G (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 81
• Phenotypes (HPO): 32

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		25	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

32 HPO clinical features (Orphanet curated; top 32 by frequency):

HPO ID	Term	Frequency
HP:0001260	Dysarthria	Very frequent (80-99%)
HP:0001317	Abnormal cerebellum morphology	Very frequent (80-99%)
HP:0002317	Unsteady gait	Very frequent (80-99%)
HP:0012759	Neurodevelopmental abnormality	Very frequent (80-99%)
HP:0000012	Urinary urgency	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0001152	Saccadic smooth pursuit	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002064	Spastic gait	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0006855	Cerebellar vermis atrophy	Frequent (30-79%)
HP:0006938	Impaired vibration sensation at ankles	Frequent (30-79%)
HP:0007979	Gaze-evoked horizontal nystagmus	Frequent (30-79%)
HP:0031166	Eyelid myokymia	Frequent (30-79%)
HP:0000020	Urinary incontinence	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000571	Hypometric saccades	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000651	Diplopia	Occasional (5-29%)
HP:0000802	Impotence	Occasional (5-29%)
HP:0002321	Vertigo	Occasional (5-29%)
HP:0002322	Resting tremor	Occasional (5-29%)
HP:0002346	Head tremor	Occasional (5-29%)
HP:0002511	Alzheimer disease	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003765	Psoriasiform dermatitis	Occasional (5-29%)
HP:0007351	Upper limb postural tremor	Occasional (5-29%)
HP:0007366	Atrophy/Degeneration affecting the brainstem	Occasional (5-29%)
HP:0012708	Reduced brain N-acetyl aspartate level by MRS	Occasional (5-29%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia type 42
Mondo ID	MONDO:0014776
EFO	EFO:0009059
OMIM	616795
Orphanet	458803
DOID	DOID:0111742
NCIT	C171269
UMLS	C4225205
MedGen	902592
GARD	0017811
Is cancer (heuristic)	no

Also known as: SCA42 · spinocerebellar ataxia 42 · spinocerebellar ataxia type 42

Data availability: 81 ClinVar variants · 6 GenCC gene-disease records · 5 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

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 42

Related subtypes (9): spinocerebellar ataxia type 31, spinocerebellar ataxia type 6, 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 45

Subtypes (1): spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits

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

81 retrieved; paginated sample, class counts are floors:

45 uncertain significance, 15 conflicting classifications of pathogenicity, 7 likely pathogenic, 7 benign, 3 likely benign, 2 benign/likely benign, 1 pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
221981	NM_018896.5(CACNA1G):c.5144G>A (p.Arg1715His)	CACNA1G	Pathogenic	criteria provided, multiple submitters, no conflicts
1027472	NM_018896.5(CACNA1G):c.3835G>A (p.Asp1279Asn)	CACNA1G	Likely pathogenic	criteria provided, single submitter
1228386	NM_018896.5(CACNA1G):c.2810C>T (p.Ser937Leu)	CACNA1G	Likely pathogenic	criteria provided, single submitter
2575085	NM_018896.5(CACNA1G):c.4593G>A (p.Met1531Ile)	CACNA1G	Likely pathogenic	criteria provided, single submitter
3256767	NM_018896.5(CACNA1G):c.4591A>T (p.Met1531Leu)	CACNA1G	Likely pathogenic	no assertion criteria provided
3382414	NM_018896.5(CACNA1G):c.4931A>T (p.Lys1644Met)	CACNA1G	Likely pathogenic	criteria provided, single submitter
3382661	NM_018896.5(CACNA1G):c.4180C>T (p.Arg1394Trp)	CACNA1G	Likely pathogenic	criteria provided, single submitter
974856	NM_018896.5(CACNA1G):c.632T>C (p.Leu211Pro)	CACNA1G	Likely pathogenic	criteria provided, single submitter
1027470	NM_018896.5(CACNA1G):c.481A>T (p.Ile161Phe)	CACNA1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1027471	NM_018896.5(CACNA1G):c.5960_5961delinsAC (p.Thr1987Asn)	CACNA1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030677	NM_018896.5(CACNA1G):c.1654T>C (p.Ser552Pro)	CACNA1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033911	NM_018896.5(CACNA1G):c.2407A>C (p.Ile803Leu)	CACNA1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1709627	NM_018896.5(CACNA1G):c.2131C>T (p.Arg711Trp)	CACNA1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2049186	NM_018896.5(CACNA1G):c.5776C>T (p.Pro1926Ser)	CACNA1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2067385	NM_018896.5(CACNA1G):c.2014C>T (p.Arg672Trp)	CACNA1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2177469	NM_018896.5(CACNA1G):c.1367G>T (p.Arg456Leu)	CACNA1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2289113	NM_018896.5(CACNA1G):c.3476G>A (p.Arg1159His)	CACNA1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2418541	NM_018896.5(CACNA1G):c.865C>T (p.Arg289Cys)	CACNA1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2901464	NM_018896.5(CACNA1G):c.3629G>A (p.Arg1210Gln)	CACNA1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3341487	NM_018896.5(CACNA1G):c.757G>A (p.Val253Met)	CACNA1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
634620	NM_018896.5(CACNA1G):c.1931G>A (p.Cys644Tyr)	CACNA1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
977088	NM_018896.5(CACNA1G):c.1888A>T (p.Ser630Cys)	CACNA1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
983328	NM_018896.5(CACNA1G):c.3197C>T (p.Ser1066Leu)	CACNA1G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030678	NM_018896.5(CACNA1G):c.4028G>A (p.Arg1343Gln)	CACNA1G	Uncertain significance	criteria provided, single submitter
1030680	NM_018896.5(CACNA1G):c.5230G>A (p.Gly1744Arg)	CACNA1G	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030681	NM_018896.5(CACNA1G):c.6944C>T (p.Pro2315Leu)	CACNA1G	Uncertain significance	criteria provided, single submitter
1033912	NM_018896.5(CACNA1G):c.2911G>T (p.Glu971Ter)	CACNA1G	Uncertain significance	criteria provided, single submitter
1033913	NM_018896.5(CACNA1G):c.7088T>C (p.Leu2363Pro)	CACNA1G	Uncertain significance	criteria provided, single submitter
1184723	NM_018896.5(CACNA1G):c.532G>A (p.Ala178Thr)	CACNA1G	Uncertain significance	criteria provided, single submitter
1191307	NM_018896.5(CACNA1G):c.1501C>T (p.His501Tyr)	CACNA1G	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
CACNA1G	Definitive	Autosomal dominant	spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CACNA1G	Orphanet:458803	Spinocerebellar ataxia type 42

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
CACNA1G	HGNC:1394	ENSG00000006283	O43497	Voltage-dependent T-type calcium channel subunit alpha-1G	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 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)
CACNA1G	Ion channel	yes		VDCCAlpha1, VDCC_T_a1, Ion_trans_dom

Expression context

Cohort genes with no expression data: 0.

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
lateral nuclear group of thalamus	1
right frontal lobe	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
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

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CACNA1G	O43497	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
NCAM signaling for neurite out-growth	1	271.9×	0.009	CACNA1G
Smooth Muscle Contraction	1	265.6×	0.009	CACNA1G
NCAM1 interactions	1	248.3×	0.009	CACNA1G
Muscle contraction	1	77.2×	0.023	CACNA1G
Axon guidance	1	45.1×	0.027	CACNA1G
Nervous system development	1	42.9×	0.027	CACNA1G
Developmental Biology	1	14.5×	0.069	CACNA1G

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
SA node cell to atrial cardiac muscle cell signaling	1	16852.0×	5e-04	CACNA1G
AV node cell to bundle of His cell signaling	1	16852.0×	5e-04	CACNA1G
response to nickel cation	1	8426.0×	6e-04	CACNA1G
AV node cell action potential	1	4213.0×	8e-04	CACNA1G
membrane depolarization during AV node cell action potential	1	3370.4×	8e-04	CACNA1G
membrane depolarization during SA node cell action potential	1	3370.4×	8e-04	CACNA1G
SA node cell action potential	1	2808.7×	8e-04	CACNA1G
sinoatrial node development	1	2106.5×	9e-04	CACNA1G
regulation of atrial cardiac muscle cell membrane depolarization	1	1872.4×	9e-04	CACNA1G
calcium ion import	1	802.5×	0.002	CACNA1G
cardiac muscle cell action potential involved in contraction	1	702.2×	0.002	CACNA1G
calcium ion import across plasma membrane	1	543.6×	0.002	CACNA1G
regulation of heart rate by cardiac conduction	1	374.5×	0.003	CACNA1G
regulation of membrane potential	1	230.8×	0.005	CACNA1G
calcium ion transmembrane transport	1	210.7×	0.005	CACNA1G
chemical synaptic transmission	1	77.3×	0.013	CACNA1G

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
CACNA1G	NIMODIPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1G	8	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIMODIPINE	4	CACNA1G
TACRINE	4	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

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: 1; 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	CACNA1G
TACRINE	4	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)	1	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.