KIF1A

Chr 2ADAR

kinesin family member 1A

Also known as: ATSV, C2orf20, HSN2C, MRD9, NESCAVS, SPG30, SPG30A, SPG30B

NCBI Gene: 547ENSG00000130294UniProt: Q12756

The protein encoded by this gene is a member of the kinesin family and functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. Mutations at this locus have been associated with spastic paraplegia-30 and hereditary sensory neuropathy IIC. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Apr 2012]

Primary Disease Associations & Inheritance

NESCAV syndromeMIM #614255
AD
Neuropathy, hereditary sensory, type IICMIM #614213
AR
Spastic paraplegia 30, autosomal dominantMIM #610357
AD
Spastic paraplegia 30, autosomal recessiveMIM #620607
AR
3584
ClinVar variants
40
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— KIF1A
⚡
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
40 Pathogenic / Likely Pathogenic· 226 VUS of 3584 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.
0.14LOEUF
pLI 1.000
Z-score 8.44
OE 0.07 (0.04–0.14)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.
5.16Z-score
OE missense 0.57 (0.53–0.61)
640 obs / 1127.3 exp
Constrained

Extremely missense-constrained (top ~0.01%)

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.0.07 (0.04–0.14)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.57 (0.53–0.61)
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.1.00
0≤1.21.6
LoF obs/exp: 7 / 96.4Missense obs/exp: 640 / 1127.3Syn Z: 0.01

ClinVar Variant Classifications

3584 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic23
VUS226
Likely Benign198
Benign3
Conflicting3
17
Pathogenic
23
Likely Pathogenic
226
VUS
198
Likely Benign
3
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
4
8
0
17
Likely Pathogenic
9
14
0
0
23
VUS
4
197
22
3
226
Likely Benign
1
7
100
90
198
Benign
0
2
1
0
3
Conflicting
—3
Total1922413193470

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

View in ClinVar →

Protein Context — Lollipop Plot

KIF1A · protein map & ClinVar variants

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

Gene2Phenotype Curations

KIF1A-related NESCAV syndrome

definitive
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

KIF1A-related neuropathy, hereditary sensory

definitive
ARLoss 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

NESCAV syndrome

MIM #614255

Molecular basis of disorder known

Autosomal dominant

Neuropathy, hereditary sensory, type IIC

MIM #614213

Molecular basis of disorder known

Autosomal recessive

Spastic paraplegia 30, autosomal dominant

MIM #610357

Molecular basis of disorder known

Autosomal dominant

Spastic paraplegia 30, autosomal recessive

MIM #620607

Molecular basis of disorder known

Autosomal recessive
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
Association of variants in the KIF1A gene with amyotrophic lateral sclerosis.
Liao P et al.·Transl Neurodegener
2022
Antisense oligonucleotide therapy in an individual with KIF1A-associated neurological disorder.
Ziegler A et al.·Nat Med
2024Case report
A de novo low-frequency mosaic variant of KIF1A causes hereditary spastic paraplegia: A literature review.
Liu M et al.·Ann Hum Genet
2023Review
Monoallelic KIF1A-related disorders: a multicenter cross sectional study and systematic literature review.
Vecchia SD et al.·J Neurol
2022Review
A Japanese Family with a Novel Pathogenic Variant in KIF1A Presenting with Spastic Paraparesis, Cerebellar Ataxia, and Intellectual Disability.
Mitsutake A et al.·Cerebellum
2024
Genetic overlap between ALS and other neurodegenerative or neuromuscular disorders.
Olsen CG et al.·Amyotroph Lateral Scler Frontotemporal Degener
2024
Long-term clinical observation of patients with heterozygous KIF1A variants.
Kawashima A et al.·Am J Med Genet A
2024Cohort
Soma-localized Rab39 inhibits synaptic autophagy by controlling trafficking of Atg9 vesicles.
Kilic A et al.·EMBO J
2025
Heterogeneity of comprehensive clinical phenotype and longitudinal adaptive function and correlation with computational predictions of severity of missense genotypes in KIF1A-associated neurological disorder.
Sudnawa KK et al.·Genet Med
2024Natural history
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
SP1 recruits TET1 to mediate Kif1a demethylation and synaptic remodeling in a mouse model of chronic migraine.
Jiang W et al.·J Headache Pain
2026Functional
Antisense oligonucleotides to KIF1A polymorphisms expand targets and rescue patient-derived neurons in vitro.
Zuccaro MV et al.·Nat Commun
2026🔓 Open Access
Genotype-phenotype correlations in 18 European patients with heterozygous KIF1A variants: key considerations for assessing KIF1A variant causality.
Uhrova Meszarosova A et al.·Front Med (Lausanne)
2025🔓 Open AccessCohort
KIF1A-associated neurological disorders: therapeutic opportunities and challenges.
Lin Q et al.·Eur J Hum Genet
2025
Allele-specific conformational rescue of KIF1A T99M by genetic suppressors in a C. elegans model of KIF1A-associated neurological disorder.
Chen Z et al.·J Cell Sci
2025Functional
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