KIF5A

Chr 12AD

kinesin family member 5A

NCBI Gene: 3798ENSG00000155980UniProt: Q12840

Microtubule-dependent motor required for slow axonal transport of neurofilament proteins (NFH, NFM and NFL). Can induce formation of neurite-like membrane protrusions in non-neuronal cells in a ZFYVE27-dependent manner. The ZFYVE27-KIF5A complex contributes to the vesicular transport of VAPA, VAPB, SURF4, RAB11A, RAB11B and RTN3 proteins in neurons. Required for anterograde axonal transportation of MAPK8IP3/JIP3 which is essential for MAPK8IP3/JIP3 function in axon elongation

Primary Disease Associations & Inheritance

{Amyotrophic lateral sclerosis, susceptibility to, 25}MIM #617921
AD
Myoclonus, intractable, neonatalMIM #617235
AD
Spastic paraplegia 10, autosomal dominantMIM #604187
AD
595
ClinVar variants
47
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— KIF5A
🧬
Gene-Disease Validity (ClinGen)
amyotrophic lateral sclerosis, susceptibility to, 25 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
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
47 Pathogenic / Likely Pathogenic· 272 VUS of 595 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.23LOEUF
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?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.
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?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.0.13 (0.07–0.23)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.58 (0.53–0.64)
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.0.93
0≤1.21.6
LoF obs/exp: 8 / 63.3Missense obs/exp: 341 / 586.2Syn Z: 0.85

ClinVar Variant Classifications

595 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20
Likely Pathogenic27
VUS272
Likely Benign248
Benign7
Conflicting21
20
Pathogenic
27
Likely Pathogenic
272
VUS
248
Likely Benign
7
Benign
21
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
8
4
0
20
Likely Pathogenic
12
7
8
0
27
VUS
2
225
38
7
272
Likely Benign
0
18
122
108
248
Benign
0
1
3
3
7
Conflicting
—21
Total22259175118595

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

View in ClinVar →

Protein Context — Lollipop Plot

KIF5A · protein map & ClinVar variants

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

Gene2Phenotype Curations

KIF5A-related severe neonatal myoclonus

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Amyotrophic lateral sclerosis, susceptibility to, 25}

MIM #617921

Molecular basis of disorder known

Autosomal dominant

Myoclonus, intractable, neonatal

MIM #617235

Molecular basis of disorder known

Autosomal dominant

Spastic paraplegia 10, autosomal dominant

MIM #604187

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — KIF5A
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
Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.
Nicolas A et al.·Neuron
2018
Altered molecular and cellular mechanisms in KIF5A-associated neurodegenerative or neurodevelopmental disorders.
Cozzi M et al.·Cell Death Dis
2024Functional
New variants and genotype-phenotype correlation in KIF5A mutation: the contribution of a large Italian cohort.
Ferese R et al.·J Med Genet
2025Cohort
The choroidal nervous system: a link between mineralocorticoid receptor and pachychoroid.
Leclercq B et al.·Acta Neuropathol
2023
The ALS-associated KIF5A P986L variant is not pathogenic for Drosophila motoneurons.
Layalle S et al.·Sci Rep
2024
The genetic and clinical spectrum in a cohort of 39 families with complex inherited peripheral neuropathies.
Wang M et al.·J Neurol
2023Cohort
Recent Updates on the Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.
Kirola L et al.·Mol Neurobiol
2022Review
Targeted plasma proteomics uncover proteins associated with KIF5A-linked SPG10 and ALS spectrum disorders.
Dulski J et al.·HGG Adv
2026
KIF5A variant in familial dystonia: A clinicogenetic study of a large Roma kindred.
Dulski J et al.·Parkinsonism Relat Disord
2025
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools