Spastic ataxia 1

Summary

Spastic ataxia 1 (MONDO:0007164) is a disease caused by VAMP1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: VAMP1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 8
• Phenotypes (HPO): 26

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		53	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0000605	Supranuclear gaze palsy	Very frequent (80-99%)
HP:0001276	Hypertonia	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0002061	Lower limb spasticity	Very frequent (80-99%)
HP:0000514	Slow saccadic eye movements	Frequent (30-79%)
HP:0001258	Spastic paraplegia	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002064	Spastic gait	Frequent (30-79%)
HP:0002070	Limb ataxia	Frequent (30-79%)
HP:0002354	Memory impairment	Frequent (30-79%)
HP:0002464	Spastic dysarthria	Frequent (30-79%)
HP:0002497	Spastic ataxia	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0006961	Jerky head movements	Frequent (30-79%)
HP:0008969	Leg muscle stiffness	Frequent (30-79%)
HP:0000492	Abnormal eyelid morphology	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0002166	Impaired vibration sensation in the lower limbs	Occasional (5-29%)
HP:0010831	Impaired proprioception	Occasional (5-29%)
HP:0002921	Abnormality of the cerebrospinal fluid	Excluded (0%)
HP:0003700	Generalized amyotrophy	Excluded (0%)
HP:0001250	Seizure	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spastic ataxia 1
Mondo ID	MONDO:0007164
MeSH	C566993
OMIM	108600
Orphanet	251282
DOID	DOID:0050772
UMLS	C1970107
MedGen	409988
GARD	0017206
Is cancer (heuristic)	no

Also known as: autosomal dominant spastic ataxia caused by mutation in VAMP1 · spastic ataxia 1, autosomal dominant · spastic ataxia type 1 · SPAX1 · VAMP1 autosomal dominant spastic ataxia

Data availability: 8 ClinVar variants · 3 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 spastic ataxia › spastic ataxia 1

Related subtypes (2): spastic ataxia 7, spastic ataxia 11, autosomal dominant

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

8 retrieved; paginated sample, class counts are floors:

3 benign, 2 pathogenic/likely pathogenic, 1 pathogenic, 1 likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1459811	NM_014231.5(VAMP1):c.97C>T (p.Arg33Ter)	TAPBPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
240888	NM_014231.5(VAMP1):c.340+2T>G	TAPBPL	Pathogenic	criteria provided, multiple submitters, no conflicts
619001	NM_014231.5(VAMP1):c.340del (p.Ile114fs)	TAPBPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2575084	NM_014231.5(VAMP1):c.152dup (p.Asn51fs)	TAPBPL	Likely pathogenic	criteria provided, single submitter
4814114	NM_014231.5(VAMP1):c.295A>G (p.Ile99Val)	TAPBPL	Uncertain significance	criteria provided, single submitter
1234868	NM_014231.5(VAMP1):c.*1588T>C	TAPBPL	Benign	criteria provided, multiple submitters, no conflicts
1280091	NM_014231.5(VAMP1):c.130-25T>A	TAPBPL	Benign	criteria provided, multiple submitters, no conflicts
995356	NM_014231.5(VAMP1):c.252C>A (p.Ala84=)	TAPBPL	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
VAMP1	Strong	Autosomal dominant	spastic ataxia 1	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VAMP1	Orphanet:251282	Autosomal dominant spastic ataxia type 1
VAMP1	Orphanet:98914	Presynaptic congenital myasthenic syndromes

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
VAMP1	HGNC:12642	ENSG00000139190	P23763	Vesicle-associated membrane protein 1	gencc
TAPBPL	HGNC:30683	ENSG00000139192	Q9BX59	Tapasin-related protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VAMP1	Vesicle-associated membrane protein 1	Involved in the targeting and/or fusion of transport vesicles to their target membrane.
TAPBPL	Tapasin-related protein	Component of the antigen processing and presentation pathway, which binds to MHC class I coupled with beta2-microglobulin/B2M.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VAMP1	Other/Unknown	no		Synaptobrevin-like, Synaptobrevin/VAMP, V_SNARE_CC
TAPBPL	Antibody/Immunoglobulin	yes		Ig/MHC_CS, Ig_C1-set, Ig_sub

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
Brodmann (1909) area 23	1
pons	1
primary visual cortex	1
granulocyte	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VAMP1	268	ubiquitous	marker	pons, Brodmann (1909) area 23, primary visual cortex
TAPBPL	258	ubiquitous	marker	granulocyte, left lobe of thyroid gland, right lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VAMP1	1,598
TAPBPL	451

Intra-cohort edges

A	B	Sources
TAPBPL	VAMP1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TAPBPL	Q9BX59	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VAMP1	P23763	75.47

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 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
Toxicity of botulinum toxin type G (botG)	1	3806.7×	4e-04	VAMP1
Toxicity of botulinum toxin type D (botD)	1	2284.0×	4e-04	VAMP1
Toxicity of botulinum toxin type F (botF)	1	2284.0×	4e-04	VAMP1

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
negative regulation of antigen processing and presentation of peptide antigen via MHC class I	1	8426.0×	5e-04	TAPBPL
peptide antigen assembly with MHC class I protein complex	1	1404.3×	0.001	TAPBPL
SNARE complex assembly	1	702.2×	0.002	VAMP1
vesicle fusion	1	300.9×	0.003	VAMP1

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
VAMP1	0	0
TAPBPL	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	1	TAPBPL
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	VAMP1

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)
VAMP1	0	—
TAPBPL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.