Spinocerebellar ataxia type 40

Summary

Spinocerebellar ataxia type 40 (MONDO:0014475) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 79
• Phenotypes (HPO): 14

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0000511	Vertical supranuclear gaze palsy	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002075	Dysdiadochokinesis	Frequent (30-79%)
HP:0002080	Intention tremor	Frequent (30-79%)
HP:0002136	Broad-based gait	Frequent (30-79%)
HP:0002167	Abnormality of speech or vocalization	Frequent (30-79%)
HP:0002168	Scanning speech	Frequent (30-79%)
HP:0002313	Spastic paraparesis	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0004302	Functional motor deficit	Frequent (30-79%)
HP:0006879	Pontocerebellar atrophy	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia type 40
Mondo ID	MONDO:0014475
OMIM	616053
Orphanet	423275
DOID	DOID:0050986
SNOMED CT	734020000
UMLS	C4518336
MedGen	1385103
GARD	0012371
Is cancer (heuristic)	no

Also known as: SCA40 · spinocerebellar ataxia 40 · spinocerebellar ataxia type 40

Data availability: 79 ClinVar variants · 5 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 cerebellar ataxia › autosomal dominant cerebellar ataxia type I › spinocerebellar ataxia type 40

Related subtypes (29): Machado-Joseph disease, spinocerebellar ataxia type 29, spinocerebellar ataxia type 34, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 4, cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome, autosomal dominant cerebellar ataxia, deafness and narcolepsy, spinocerebellar ataxia type 12, spinocerebellar ataxia type 13, spinocerebellar ataxia type 14, spinocerebellar ataxia type 15/16, spinocerebellar ataxia type 17, spinocerebellar ataxia type 19/22, spinocerebellar ataxia type 21, spinocerebellar ataxia type 18, spinocerebellar ataxia type 20, spinocerebellar ataxia type 25, spinocerebellar ataxia type 8, spinocerebellar ataxia type 27, spinocerebellar ataxia type 23, spinocerebellar ataxia type 28, spinocerebellar ataxia type 35, spinocerebellar ataxia type 32, spinocerebellar ataxia type 36, cerebellar dysfunction with variable cognitive and behavioral abnormalities, spinocerebellar ataxia type 37, spinocerebellar ataxia 46, neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism

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

79 retrieved; paginated sample, class counts are floors:

25 uncertain significance, 24 likely pathogenic, 9 benign, 9 benign/likely benign, 7 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2841702	NM_001080414.4(CCDC88C):c.1702C>T (p.Arg568Ter)	CCDC88C	Pathogenic	criteria provided, single submitter
2956067	NM_001080414.4(CCDC88C):c.1420_1421del (p.Ser474fs)	CCDC88C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2957330	NM_001080414.4(CCDC88C):c.5101C>T (p.Arg1701Ter)	CCDC88C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2993938	NM_001080414.4(CCDC88C):c.5273_5276del (p.Thr1758fs)	CCDC88C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39861	NM_001080414.4(CCDC88C):c.934C>T (p.Arg312Ter)	CCDC88C	Pathogenic	criteria provided, multiple submitters, no conflicts
2846535	NM_001080414.4(CCDC88C):c.4442-2A>G	CCDC88C	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3576880	NM_001080414.4(CCDC88C):c.5250C>G (p.Tyr1750Ter)	CCDC88C	Likely pathogenic	criteria provided, single submitter
3576881	NM_001080414.4(CCDC88C):c.5132dup (p.Gln1712fs)	CCDC88C	Likely pathogenic	criteria provided, single submitter
3576882	NM_001080414.4(CCDC88C):c.4768+1G>T	CCDC88C	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3576884	NM_001080414.4(CCDC88C):c.4113-1_4117del	CCDC88C	Likely pathogenic	criteria provided, single submitter
3576885	NM_001080414.4(CCDC88C):c.4096G>T (p.Glu1366Ter)	CCDC88C	Likely pathogenic	criteria provided, single submitter
3576886	NM_001080414.4(CCDC88C):c.4090_4093delinsATT (p.His1364fs)	CCDC88C	Likely pathogenic	criteria provided, single submitter
3576887	NM_001080414.4(CCDC88C):c.3796del (p.His1266fs)	CCDC88C	Likely pathogenic	criteria provided, single submitter
3576889	NM_001080414.4(CCDC88C):c.3550G>T (p.Glu1184Ter)	CCDC88C	Likely pathogenic	criteria provided, single submitter
3576890	NM_001080414.4(CCDC88C):c.3358-2A>C	CCDC88C	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3576891	NM_001080414.4(CCDC88C):c.3310del (p.Leu1104fs)	CCDC88C	Likely pathogenic	criteria provided, single submitter
3576892	NM_001080414.4(CCDC88C):c.3195+1G>T	CCDC88C	Likely pathogenic	criteria provided, single submitter
3576893	NM_001080414.4(CCDC88C):c.3166_3167insT (p.Lys1056fs)	CCDC88C	Likely pathogenic	criteria provided, single submitter
3576895	NM_001080414.4(CCDC88C):c.3013A>T (p.Lys1005Ter)	CCDC88C	Likely pathogenic	criteria provided, single submitter
3576896	NM_001080414.4(CCDC88C):c.2903dup (p.Leu968fs)	CCDC88C	Likely pathogenic	criteria provided, single submitter
3576897	NM_001080414.4(CCDC88C):c.2206dup (p.Glu736fs)	CCDC88C	Likely pathogenic	criteria provided, single submitter
3576898	NM_001080414.4(CCDC88C):c.1637del (p.Glu546fs)	CCDC88C	Likely pathogenic	criteria provided, single submitter
3576900	NM_001080414.4(CCDC88C):c.613G>T (p.Glu205Ter)	CCDC88C	Likely pathogenic	criteria provided, single submitter
3576902	NM_001080414.4(CCDC88C):c.483+1G>T	CCDC88C	Likely pathogenic	criteria provided, single submitter
3576903	NM_001080414.4(CCDC88C):c.340+1G>T	CCDC88C	Likely pathogenic	criteria provided, single submitter
3576904	NM_001080414.4(CCDC88C):c.105_108del (p.Thr36fs)	CCDC88C	Likely pathogenic	criteria provided, single submitter
3576905	NM_001080414.4(CCDC88C):c.99_100insGGTT (p.Asn34delinsGlyTer)	CCDC88C	Likely pathogenic	criteria provided, single submitter
524092	NM_001080414.4(CCDC88C):c.755dup (p.Ala253fs)	CCDC88C	Likely pathogenic	criteria provided, multiple submitters, no conflicts
978819	NM_001080414.4(CCDC88C):c.1993G>A (p.Glu665Lys)	CCDC88C	Likely pathogenic	criteria provided, single submitter
2163153	NM_001080414.4(CCDC88C):c.5209G>A (p.Ala1737Thr)	CCDC88C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 3 · 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
CCDC88C	Moderate	Autosomal dominant	spinocerebellar ataxia type 40	8
CCDC8	Limited	Autosomal dominant	spinocerebellar ataxia type 40	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CCDC88C	Orphanet:269510	Congenital non-communicating hydrocephalus
CCDC88C	Orphanet:423275	Spinocerebellar ataxia type 40
CCDC8	Orphanet:2616	3M syndrome

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
CCDC88C	HGNC:19967	ENSG00000015133	Q9P219	Protein Daple	gencc,clinvar
CCDC8	HGNC:25367	ENSG00000169515	Q9H0W5	Coiled-coil domain-containing protein 8	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CCDC88C	Protein Daple	Required for activation of guanine nucleotide-binding proteins (G-proteins) during non-canonical Wnt signaling.
CCDC8	Coiled-coil domain-containing protein 8	Core component of the 3M complex, a complex required to regulate microtubule dynamics and genome integrity.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CCDC88C	Other/Unknown	no		CH_dom, CH_dom_sf, HOOK_N
CCDC8	Other/Unknown	no		CCDC8

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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
granulocyte	1
olfactory segment of nasal mucosa	1
right uterine tube	1
cardiac muscle of right atrium	1
kidney epithelium	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CCDC88C	220	ubiquitous	marker	right uterine tube, granulocyte, olfactory segment of nasal mucosa
CCDC8	213	ubiquitous	marker	kidney epithelium, upper arm skin, cardiac muscle of right atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CCDC8	3,061
CCDC88C	906

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CCDC8	Q9H0W5	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CCDC88C	Q9P219	65.69

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Negative regulation of TCF-dependent signaling by DVL-interacting proteins	1	1142.0×	0.004	CCDC88C
Neddylation	1	23.7×	0.084	CCDC8
Post-translational protein modification	1	9.6×	0.135	CCDC8
Metabolism of proteins	1	6.2×	0.155	CCDC8

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
respiratory basal cell differentiation	1	4213.0×	0.004	CCDC88C
apical constriction	1	1685.2×	0.005	CCDC88C
mucociliary clearance	1	648.1×	0.007	CCDC88C
cytoskeleton-dependent intracellular transport	1	468.1×	0.007	CCDC88C
regulation of mitotic nuclear division	1	312.1×	0.007	CCDC8
cilium organization	1	300.9×	0.007	CCDC88C
non-canonical Wnt signaling pathway	1	290.6×	0.007	CCDC88C
microtubule bundle formation	1	255.3×	0.007	CCDC88C
negative regulation of microtubule depolymerization	1	247.8×	0.007	CCDC88C
Wnt signaling pathway, planar cell polarity pathway	1	227.7×	0.007	CCDC88C
cytoplasmic microtubule organization	1	172.0×	0.008	CCDC88C
protein destabilization	1	145.3×	0.009	CCDC88C
small GTPase-mediated signal transduction	1	91.6×	0.013	CCDC88C
positive regulation of JNK cascade	1	81.8×	0.014	CCDC88C
microtubule cytoskeleton organization	1	60.6×	0.017	CCDC8
negative regulation of canonical Wnt signaling pathway	1	58.9×	0.017	CCDC88C

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CCDC88C	0	0
CCDC8	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	2	CCDC88C, CCDC8

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CCDC88C	0	—
CCDC8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.