SPAST

Chr 2AD

spastin

Also known as: ADPSP, FSP2, SPG4

NCBI Gene: 6683 ENSG00000021574 UniProt: Q9UBP0 OMIM: 604277

The protein functions as a microtubule-severing enzyme that regulates microtubule abundance, mobility, and plus-end distribution, and is a member of the AAA ATPase family involved in diverse cellular processes including membrane trafficking and intracellular motility. Loss-of-function mutations cause autosomal dominant spastic paraplegia 4, which is the most common form of hereditary spastic paraplegia. The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the disease mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

LOFmechanismADLOEUF 0.221 OMIM phenotype

Clinical Summary— SPAST

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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.

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ClinVar Variants

489 unique Pathogenic / Likely Pathogenic· 348 VUS of 1100 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SPAST

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE0.09 (0.04–0.22)

0≤0.351.4

Missense OE0.81 (0.73–0.90)

0≤0.61.4

Synonymous OE1.27

0≤1.21.6

LoF obs/exp: 3 / 34.6Missense obs/exp: 279 / 343.9Syn Z: -2.36

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSPAST-related spastic paraplegiaLOFAD

strongSPAST-related developmental disorderOTHERAD

0.4983th %ile

GOF

0.4776th %ile

LOF

0.68top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 58% of P/LP variants are LoF · LOEUF 0.22

GOF1 literature citation

Literature Evidence

GOFMutations of the SPAST gene, which encodes the microtubule-severing protein spastin, are the most common cause of hereditary spastic paraplegia (HSP). Haploinsufficiency is the prevalent opinion as to the mechanism of the disease, but gain-of-function toxicity of the mutant proteins is another possiPMID:30520996

LOFClassical mutations in the most frequent HSP gene SPAST (spastin protein) act through haploinsufficiency by abolishing the activity of a C-terminal ATPase domain or by interfering with expression from the affected allele.PMID:17916079

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.