SPAST

Chr 2AD

spastin

Also known as: ADPSP, FSP2, SPG4

NCBI Gene: 6683ENSG00000021574UniProt: Q9UBP0

This gene encodes a member of the AAA (ATPases associated with a variety of cellular activities) protein family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. The use of alternative translational initiation sites in this gene results in a single transcript variant that can produce isoforms that differ in the length of their N-terminus and which thereby differ in the efficiency of their export from the nucleus to the cytoplasm. In addition, alternative splicing results in multiple transcript variants that encode isoforms that differ in other protein regions as well. One isoform of this gene has been shown to be a microtubule-severing enzyme that regulates microtubule abundance, mobility, and plus-end distribution. Mutations in this gene cause the most frequent form of autosomal dominant spastic paraplegia 4. [provided by RefSeq, May 2018]

Primary Disease Associations & Inheritance

Spastic paraplegia 4, autosomal dominantMIM #182601
AD
481
ClinVar variants
168
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— SPAST
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
168 Pathogenic / Likely Pathogenic· 200 VUS of 481 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.22LOEUF
pLI 0.999
Z-score 4.97
OE 0.09 (0.04–0.22)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.24Z-score
OE missense 0.81 (0.73–0.90)
279 obs / 343.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.09 (0.04–0.22)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.81 (0.73–0.90)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.27
0≤1.21.6
LoF obs/exp: 3 / 34.6Missense obs/exp: 279 / 343.9Syn Z: -2.36

ClinVar Variant Classifications

481 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic118
Likely Pathogenic50
VUS200
Likely Benign99
Benign7
Conflicting7
118
Pathogenic
50
Likely Pathogenic
200
VUS
99
Likely Benign
7
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
60
4
54
0
118
Likely Pathogenic
22
20
8
0
50
VUS
3
163
31
3
200
Likely Benign
2
9
39
49
99
Benign
0
0
7
0
7
Conflicting
—7
Total8719613952481

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SPAST · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SPAST-related spastic paraplegia

definitive
ADLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure
Dev. Disorders
G2P ↗
splice region variantframeshift variantstop gainedmissense variantintron variantwhole partial gene deletion

SPAST-related developmental disorder

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
SPASTIN; SPAST
MIM #604277 · *

Spastic paraplegia 4, autosomal dominant

MIM #182601

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SPAST
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical and genetic spectra of 1550 index patients with hereditary spastic paraplegia.
Méreaux JL et al.·Brain
2022Cohort
Mendelian etiologies identified with whole exome sequencing in cerebral palsy.
Chopra M et al.·Ann Clin Transl Neurol
2022
A novel truncated variant in SPAST results in spastin accumulation and defects in microtubule dynamics.
Wang J et al.·BMC Med Genomics
2023
A p.Arg499His mutation in SPAST is associated with infantile-onset complicated spastic paraplegia: a case report and review of the literature.
Nan H et al.·BMC Neurol
2021Review
Detection of novel mutations and review of published data suggests that hereditary spastic paraplegia caused by spastin (SPAST) mutations is found more often in males.
Proukakis C et al.·J Neurol Sci
2011Review
Childhood-Onset Hereditary Spastic Paraplegia (HSP): A Case Series and Review of Literature.
Panwala TF et al.·Pediatr Neurol
2022Review
Expanding Hereditary Spastic Paraplegias Limits: Biallelic SPAST Variants in Cerebral Palsy Mimics.
Nolasco GA et al.·Ann Clin Transl Neurol
2026
Early-Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST.
Mo A et al.·Mov Disord
2022
Clinically Relevant Genes Identified in Cerebral Palsy Cohorts Following Evaluation of the Clinical Description and Phenotype: A Systematic Review.
Wilson YA et al.·J Child Neurol
2024Review
Store-operated calcium entry is reduced in spastin-linked hereditary spastic paraplegia.
Rizo T et al.·Brain
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools