KIF5A

Chr 12AD

kinesin family member 5A

Also known as: ALS25, D12S1889, MY050, NEIMY, NKHC, SPG10

NCBI Gene: 3798 ENSG00000155980 UniProt: Q12840 OMIM: 602821

This protein functions as a microtubule motor that transports intracellular organelles throughout the cytoplasm. Mutations cause autosomal dominant spastic paraplegia 10, intractable neonatal myoclonus, and increase susceptibility to amyotrophic lateral sclerosis. The pathogenic mechanism involves disrupted intracellular transport due to impaired motor protein function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismADLOEUF 0.233 OMIM phenotypes

Clinical Summary— KIF5A

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Gene-Disease Validity (ClinGen)

amyotrophic lateral sclerosis, susceptibility to, 25 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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

31 unique Pathogenic / Likely Pathogenic· 241 VUS of 500 total submissions

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GeneReview available — KIF5A

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.23LOEUF

pLI 1.000

Z-score 6.44

OE 0.13 (0.07–0.23)

Highly constrained

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

Missense Constraint

3.60Z-score

OE missense 0.58 (0.53–0.64)

341 obs / 586.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.13 (0.07–0.23)

0≤0.351.4

Missense OE0.58 (0.53–0.64)

0≤0.61.4

Synonymous OE0.93

0≤1.21.6

LoF obs/exp: 8 / 63.3Missense obs/exp: 341 / 586.2Syn Z: 0.85

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKIF5A-related severe neonatal myoclonusLOFAD

0.6647th %ile

GOF

0.5563th %ile

LOF

0.60top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 74% of P/LP variants are LoF · LOEUF 0.23

DNprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNOur results imply that SPG10 is not caused by haploinsufficiency but by the loss of endogenous kinesin-1 function due to a selective dominant-negative action of mutant KIF5A on kinesin-1 complexes.PMID:23209432

LOFWe additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the mosPMID:29342275

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