Spinocerebellar ataxia type 21

Summary

Spinocerebellar ataxia type 21 (MONDO:0011833) is a disease caused by TMEM240 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TMEM240 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 15
• Phenotypes (HPO): 15
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		35	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0002066	Gait ataxia	Very frequent (80-99%)
HP:0002071	Abnormality of extrapyramidal motor function	Very frequent (80-99%)
HP:0002073	Progressive cerebellar ataxia	Very frequent (80-99%)
HP:0007944	Intermittent microsaccadic pursuits	Very frequent (80-99%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0002063	Rigidity	Frequent (30-79%)
HP:0002304	Akinesia	Frequent (30-79%)
HP:0006855	Cerebellar vermis atrophy	Frequent (30-79%)
HP:0010526	Dysgraphia	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000651	Diplopia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia type 21
Mondo ID	MONDO:0011833
MeSH	C537200
OMIM	607454
Orphanet	98773
DOID	DOID:0050972
ICD-11	1426889593
SNOMED CT	718774001
UMLS	C1843891
MedGen	375311
GARD	0009999
Is cancer (heuristic)	no

Also known as: SCA21 · spinocerebellar ataxia 21 · spinocerebellar ataxia type 21

Data availability: 15 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 I › spinocerebellar ataxia type 21

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 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 type 40, 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

15 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 5 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
161192	NM_001114748.2(TMEM240):c.509C>T (p.Pro170Leu)	TMEM240	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
161193	NM_001114748.2(TMEM240):c.489C>G (p.Tyr163Ter)	TMEM240	Pathogenic	no assertion criteria provided
1027486	NM_001114748.2(TMEM240):c.419T>A (p.Leu140Gln)	TMEM240	Likely pathogenic	criteria provided, single submitter
161195	NM_001114748.2(TMEM240):c.239C>T (p.Thr80Met)	TMEM240	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
161196	NM_001114748.2(TMEM240):c.511C>T (p.Arg171Trp)	TMEM240	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2437114	NM_001114748.2(TMEM240):c.217G>A (p.Ala73Thr)	TMEM240	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
372833	NM_001114748.2(TMEM240):c.196G>A (p.Gly66Arg)	TMEM240	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
523023	NM_001114748.2(TMEM240):c.343G>A (p.Val115Met)	TMEM240	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1355911	NM_001114748.2(TMEM240):c.35T>C (p.Ile12Thr)	TMEM240	Uncertain significance	criteria provided, multiple submitters, no conflicts
161194	NM_001114748.2(TMEM240):c.346C>T (p.Arg116Cys)	TMEM240	Uncertain significance	criteria provided, multiple submitters, no conflicts
2158528	NM_001114748.2(TMEM240):c.265G>A (p.Asp89Asn)	TMEM240	Uncertain significance	criteria provided, multiple submitters, no conflicts
2412693	NM_001114748.2(TMEM240):c.47C>A (p.Ser16Ter)	TMEM240	Uncertain significance	criteria provided, single submitter
2437113	NM_001114748.2(TMEM240):c.328G>A (p.Val110Ile)	TMEM240	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892664	NM_001114748.2(TMEM240):c.1A>G (p.Met1Val)	TMEM240	Uncertain significance	criteria provided, single submitter
4531975	NM_001114748.2(TMEM240):c.487dup (p.Tyr163fs)	TMEM240	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
TMEM240	Definitive	Autosomal dominant	spinocerebellar ataxia type 21	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM240	Orphanet:98773	Spinocerebellar ataxia type 21

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
TMEM240	HGNC:25186	ENSG00000205090	Q5SV17	Transmembrane protein 240	gencc,clinvar

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMEM240	Other/Unknown	no		TMEM240

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
cerebellar hemisphere	1
cerebellum	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM240	129	broad	yes	right hemisphere of cerebellum, cerebellar hemisphere, cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TMEM240	326

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMEM240	Q5SV17	58.48

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
TMEM240	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	TMEM240

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)
TMEM240	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