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…

Primary Disease Associations & Inheritance

{Amyotrophic lateral sclerosis, susceptibility to, 25}MIM #617921

Myoclonus, intractable, neonatalMIM #617235

Spastic paraplegia 10, autosomal dominantMIM #604187

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · inherited neurodegenerative disorder · AD · ClinGen 2023
Definitive · amyotrophic lateral sclerosis, susceptibility to, 25 · AD · ClinGen 2022
Definitive · myoclonus, intractable, neonatal · AD · G2P
Strong · hereditary spastic paraplegia 10 · AD · Ambry Genetics

+1 more curated pair

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.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.23

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

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

Background carrier burden — how many people carry a rare variant somewhere in KIF5A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 85

1,070 rare PASS variants

Rare truncating (LoF)

1 in 2,100

87 rare PASS variants

Rare synonymous (reference)

1 in 92

507 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KIF5A. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 92	1 in 2,300
South Asian	~43k	1 in 53	1 in 2,300
Remaining (unassigned)	~30k	1 in 68	1 in 4,700
European (Finnish)	~27k	1 in 150	1 in 1,600
Admixed American	~22k	1 in 60	1 in 3,300
African / African American	~21k	1 in 74	1 in 670
East Asian	~20k	1 in 81	1 in 1,100
Ashkenazi Jewish	~13k	1 in 210	1 in 1,400
Middle Eastern	~2,884	1 in 75	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 26 of 28 coding exons well covered in gnomAD exomes; exons 4, 27 marginal. Genomes: 27 of 28 (exon 8 below).? see exons ↓