Spinocerebellar ataxia type 5

Summary

Spinocerebellar ataxia type 5 (MONDO:0010848) is a disease caused by SPTBN2 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SPTBN2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 117
• Phenotypes (HPO): 4
• Clinical trials: 1

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)

4 HPO clinical features (Orphanet curated; top 4 by frequency):

HPO ID	Term	Frequency
HP:0001272	Cerebellar atrophy	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001350	Slurred speech	Very frequent (80-99%)
HP:0002311	Incoordination	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia type 5
Mondo ID	MONDO:0010848
OMIM	600224
Orphanet	98766
DOID	DOID:0050882
ICD-11	78905851
SNOMED CT	719302009
UMLS	C0752123
MedGen	155705
GARD	0004953
Is cancer (heuristic)	no

Also known as: SCA5 · spinocerebellar ataxia 5 · spinocerebellar ataxia type 5

Data availability: 117 ClinVar variants · 6 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 III › spinocerebellar ataxia type 5

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

117 retrieved; paginated sample, class counts are floors:

45 uncertain significance, 32 conflicting classifications of pathogenicity, 14 benign/likely benign, 11 likely pathogenic, 7 benign, 4 pathogenic, 3 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2500212	NM_006946.4(SPTBN2):c.5581del (p.Asp1861fs)	SPTBN2	Pathogenic	criteria provided, single submitter
279901	NM_006946.4(SPTBN2):c.1261_1263del (p.Glu421del)	SPTBN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
448482	NM_006946.4(SPTBN2):c.1596_1634del (p.Glu532_Met544del)	SPTBN2	Pathogenic	criteria provided, multiple submitters, no conflicts
5274	NM_006946.4(SPTBN2):c.1886_1900del (p.Leu629_Arg634delinsTrp)	SPTBN2	Pathogenic	no assertion criteria provided
5275	NM_006946.4(SPTBN2):c.758T>C (p.Leu253Pro)	SPTBN2	Pathogenic	criteria provided, single submitter
546676	NM_006946.4(SPTBN2):c.1310G>A (p.Arg437Gln)	SPTBN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
928964	NM_006946.4(SPTBN2):c.1309C>T (p.Arg437Trp)	SPTBN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1029115	NM_006946.4(SPTBN2):c.4358A>T (p.Asp1453Val)	SPTBN2	Likely pathogenic	criteria provided, single submitter
1029118	NM_006946.4(SPTBN2):c.812C>T (p.Thr271Ile)	SPTBN2	Likely pathogenic	criteria provided, single submitter
1333225	NM_006946.4(SPTBN2):c.5974C>T (p.Gln1992Ter)	SPTBN2	Likely pathogenic	criteria provided, single submitter
1676238	NM_006946.4(SPTBN2):c.193A>C (p.Lys65Gln)	SPTBN2	Likely pathogenic	criteria provided, single submitter
226117	NM_006946.4(SPTBN2):c.470T>C (p.Ile157Thr)	SPTBN2	Likely pathogenic	criteria provided, single submitter
3374727	NM_006946.4(SPTBN2):c.1896_1904del (p.Arg634_Arg636del)	SPTBN2	Likely pathogenic	criteria provided, single submitter
4277480	NM_006946.4(SPTBN2):c.194A>C (p.Lys65Thr)	SPTBN2	Likely pathogenic	criteria provided, single submitter
450038	NM_006946.4(SPTBN2):c.1307T>C (p.Met436Thr)	SPTBN2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4819059	NM_006946.4(SPTBN2):c.485T>C (p.Ile162Thr)	SPTBN2	Likely pathogenic	criteria provided, single submitter
804247	NM_006946.4(SPTBN2):c.1276_1278del (p.Leu426del)	SPTBN2	Likely pathogenic	criteria provided, single submitter
807500	NM_006946.4(SPTBN2):c.1052G>C (p.Arg351Pro)	SPTBN2	Likely pathogenic	criteria provided, single submitter
1027423	NM_006946.4(SPTBN2):c.5066G>A (p.Arg1689His)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1256191	NM_006946.4(SPTBN2):c.7039C>T (p.Arg2347Trp)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1298298	NM_006946.4(SPTBN2):c.1522A>C (p.Asn508His)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1400209	NM_006946.4(SPTBN2):c.2216G>A (p.Arg739His)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1566412	NM_006946.4(SPTBN2):c.5495T>G (p.Leu1832Arg)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1687336	NM_006946.4(SPTBN2):c.2558C>T (p.Ala853Val)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1802192	NM_006946.4(SPTBN2):c.6230C>T (p.Ala2077Val)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1803013	NM_006946.4(SPTBN2):c.7040G>A (p.Arg2347Gln)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195271	NM_006946.4(SPTBN2):c.157+5G>A	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2416907	NM_006946.4(SPTBN2):c.5305C>T (p.Arg1769Trp)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2996372	NM_006946.4(SPTBN2):c.6953C>T (p.Ser2318Leu)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305538	NM_006946.4(SPTBN2):c.6242G>A (p.Arg2081Gln)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
SPTBN2	Definitive	Autosomal dominant	spinocerebellar ataxia type 5	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPTBN2	Orphanet:352403	Spectrin-associated autosomal recessive cerebellar ataxia
SPTBN2	Orphanet:98766	Spinocerebellar ataxia type 5

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
SPTBN2	HGNC:11276	ENSG00000173898	O15020	Spectrin beta chain, non-erythrocytic 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPTBN2	Spectrin beta chain, non-erythrocytic 2	Probably plays an important role in neuronal membrane skeleton.

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)
SPTBN2	Scaffold/PPI	no		Actinin_actin-bd_CS, PH_dom-spectrin-type, CH_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
SPTBN2	238	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPTBN2	1,735

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SPTBN2	O15020	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. 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
Interaction between L1 and Ankyrins	1	368.4×	0.026	SPTBN2
NCAM signaling for neurite out-growth	1	271.9×	0.026	SPTBN2
ER to Golgi Anterograde Transport	1	132.8×	0.026	SPTBN2
MAPK1/MAPK3 signaling	1	131.3×	0.026	SPTBN2
L1CAM interactions	1	120.2×	0.026	SPTBN2
COPI-mediated anterograde transport	1	109.8×	0.026	SPTBN2
MAPK family signaling cascades	1	102.9×	0.026	SPTBN2
Transport to the Golgi and subsequent modification	1	102.9×	0.026	SPTBN2
MHC class II antigen presentation	1	89.2×	0.026	SPTBN2
RAF/MAP kinase cascade	1	61.1×	0.032	SPTBN2
Asparagine N-linked glycosylation	1	60.1×	0.032	SPTBN2
Axon guidance	1	45.1×	0.038	SPTBN2
Nervous system development	1	42.9×	0.038	SPTBN2
Membrane Trafficking	1	37.1×	0.040	SPTBN2
Vesicle-mediated transport	1	34.8×	0.040	SPTBN2
Adaptive Immune System	1	29.8×	0.044	SPTBN2
Post-translational protein modification	1	19.2×	0.064	SPTBN2
Developmental Biology	1	14.5×	0.081	SPTBN2
Immune System	1	13.0×	0.085	SPTBN2
Metabolism of proteins	1	12.4×	0.085	SPTBN2
Signal Transduction	1	10.2×	0.098	SPTBN2

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
cerebellar Purkinje cell layer morphogenesis	1	8426.0×	9e-04	SPTBN2
regulation of postsynaptic specialization assembly	1	4213.0×	9e-04	SPTBN2
actin filament capping	1	1532.0×	0.002	SPTBN2
adult behavior	1	468.1×	0.004	SPTBN2
synapse assembly	1	230.8×	0.007	SPTBN2
multicellular organism growth	1	137.0×	0.010	SPTBN2
vesicle-mediated transport	1	96.3×	0.012	SPTBN2
actin cytoskeleton organization	1	79.1×	0.013	SPTBN2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
SPTBN2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	1	SPTBN2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SPTBN2	0	—

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