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

This gene encodes a member of the kinesin family of proteins. Members of this family are part of a multisubunit complex that functions as a microtubule motor in intracellular organelle transport. Mutations in this gene cause autosomal dominant spastic paraplegia 10. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

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

99 unique Pathogenic / Likely Pathogenic· 603 VUS of 1514 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — KIF5A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE?0.13 (0.07–0.23)

0≤0.351.4

Missense OE?0.58 (0.53–0.64)

0≤0.61.4

Synonymous OE?0.93

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

This gene — mechanism propensity

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 · 55% 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.1

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 mos2

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

References

ClinVar Variant Classifications

1514 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic41

Likely Pathogenic58

VUS603

Likely Benign663

Benign53

Conflicting91

Pathogenic

Likely Pathogenic

603

VUS

663

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	26	12	3	0	41
Likely Pathogenic	28	29	1	0	58
VUS	9	511	69	14	603
Likely Benign	0	60	311	292	663
Benign	0	3	45	5	53
Conflicting	—				91
Total	63	615	429	311	1,509

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap KIF5A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →