SPAST

Chr 2

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]

GeneReviewsResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtSpastic paraplegia 4, autosomal dominant

Clinical highlights

Interpreting a novel variant
Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.
1
Active trials
48
Pubs (1 yr)
—
P/LP submissions
—
P/LP missense
0.22
LOEUF· LoF intol.
LOF
Mechanism· G2P
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GeneReview available — SPAST
Authoritative clinical overview · Recommended first read
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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?
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?
1.24Z-score
OE missense 0.81 (0.73–0.90)
279 obs / 343.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?
LoF OE?0.09 (0.04–0.22)
0≤0.351.4
Missense OE?0.81 (0.73–0.90)
0≤0.61.4
Synonymous OE?1.27
0≤1.21.6
LoF obs/exp: 3 / 34.6Missense obs/exp: 279 / 343.9Syn Z: -2.36

ClinVar Variant Classifications

0 submitted variants in ClinVar

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.

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients