GeneBe

KIF1A

protein-coding

kinesin family member 1A, the group of Pleckstrin homology domain containing|Kinesins

Gene summary

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]

Previous symbols:
  • ATSV
  • C2orf20
  • SPG30

MANE transcript

NM_001244008.2

Inheritance

AR, AD

ClinVar variants

P:233U:1077B:998

Top phenotype

NESCAV syndrome; Neuropathy, hereditary sensory, type IIC; Spastic paraplegia 30A, autosomal dominant; Spastic paraplegia 30B, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr2:240,713,761-240,824,293

External References & Databases

Ensembl (ENSG00000130294)NCBI Gene (547)OMIM (601255)HGNC:888GenCCUniProt (Q12756)AlphaFoldClinVar (KIF1A)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~110.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neuropathy, hereditary sensory, type 2CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013634

Submitter: PanelApp Australia

spastic paraplegia 30A, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700307

Submitter: PanelApp Australia

intellectual disability, autosomal dominant 9MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013656

Submitter: Ambry Genetics

neuropathy, hereditary sensory, type 2CLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013634

Submitter: Ambry Genetics

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

KIF1A was first reported in relation to autosomal dominant syndromic intellectual disability in 2011 (Hamdan, et al., PMID: 21376300). Affected individuals present with global developmental delay, spasticity, and variable intellectual disability. Additional features may include optic atrophy, peripheral neuropathy, seizures, ataxia, cerebellar atrophy, and cerebral atrophy. More than 70 pathogenic or likely pathogenic variants in KIF1A have been reported in ClinVar; the majority of the variants are missense and are enriched in the motor domain of KIF1A protein. Evidence supporting this gene-disease relationship includes case-level data and experimental data. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The gene-disease relationship is also supported by an animal model. Of note, recent findings suggested that KIF1A-related disorders constitute a wide phenotypic spectrum (Nemani, et al., PMID: 32096284). Defects in the KIF1A gene may result in 1) NESCAV (neurodegeneration and spasticity with or without cerebellar atrophy or cortical visual impairment) syndrome, 2) Neuropathy, hereditary sensory, type IIC, 3) Spastic paraplegia 30, autosomal dominant, and 4) Spastic paraplegia 30, autosomal recessive (see OMIM). In summary, KIF1A is definitively associated with autosomal dominant syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 8/02/20 (SOP Version 7).

hereditary spastic paraplegia 30STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012476

Submitter: Ambry Genetics

hereditary spastic paraplegia 30STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012476

Submitter: Ambry Genetics

hereditary spastic paraplegia 30STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012476

Submitter: Labcorp Genetics (formerly Invitae)

intellectual disability, autosomal dominant 9STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013656

Submitter: PanelApp Australia

PEHO syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009841

Submitter: Orphanet

hereditary spastic paraplegia 30SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012476

Submitter: Orphanet

intellectual disability, autosomal dominant 9STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013656

Submitter: Labcorp Genetics (formerly Invitae)

hereditary sensory and autonomic neuropathy type 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019941

Submitter: Orphanet

spastic paraplegia 30A, autosomal dominantSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0700307

Submitter: PanelApp Australia

hereditary spastic paraplegia 30STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012476

Submitter: Labcorp Genetics (formerly Invitae)

neuropathy, hereditary sensory, type 2CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013634

Submitter: G2P

autosomal dominant non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015802

Submitter: Orphanet

neuropathy, hereditary sensory, type 2CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013634

Submitter: Labcorp Genetics (formerly Invitae)

intellectual disability, autosomal dominant 9DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013656

Submitter: G2P

Clinical Genomic Database (CGD)

NESCAV syndrome; Neuropathy, hereditary sensory, type IIC; Spastic paraplegia 30A, autosomal dominant; Spastic paraplegia 30B, autosomal recessiveAD/AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Insensitivity to pain can result in injuries and infections

Refs: 21376300; 21487076; 21820098; 22258533Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KIF1A variants in ClinVar

31 Conditions Cataloged
Intellectual disability, autosomal dominant 9Total: 2715
Hereditary spastic paraplegia 30Total: 2709
Neuropathy, hereditary sensory, type 2CTotal: 2660
not providedTotal: 855
Inborn genetic diseasesTotal: 390
not specifiedTotal: 225
KIF1A-related disorderTotal: 113
Hereditary spastic paraplegiaTotal: 91

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001244008.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
32
clinvar
718
clinvar
21
clinvar
 771
missense
37
clinvar
126
clinvar
1029
clinvar
251
clinvar
8
clinvar
 1451
nonsense
11
clinvar
7
clinvar
5
clinvar
 23
start loss
1
clinvar
 1
frameshift
18
clinvar
3
clinvar
5
clinvar
 26
splice donor/acceptor (+/-2bp)
9
clinvar
22
clinvar
5
clinvar
 36
Total751581077969292308

Highest pathogenic variant AF is 0.00006258885

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 90 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001244008.2RefSeqNP_001230937.148MANE Select
ENST00000498729.9EnsemblENSP00000438388.148MANE Select
NM_001320705.2RefSeqNP_001307634.147Standard
NM_001330289.2RefSeqNP_001317218.148Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Vesicle-mediated transport
  • Membrane Trafficking
  • Kinesins
  • Factors involved in megakaryocyte development and platelet production
  • Hemostasis

Biological Process

  • microtubule-based movement
  • anterograde axonal transport
  • vesicle-mediated transport
  • interkinetic nuclear migration
  • cytoskeleton-dependent intracellular transport

Molecular Function

  • motor activity
  • microtubule motor activity
  • ATP binding
  • microtubule binding
  • ATP-dependent microtubule motor activity, plus-end-directed

Cellular Component

  • cytosol
  • kinesin complex
  • microtubule
  • synaptic vesicle
  • axon

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000498729
Coding exons
48
Length
106545
Individuals with no LoFs
124789
Homozygous LoFs
0
Heterozygous LoFs
8
Defined
124797
p
0.0000321
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense5.166401.13e+30.5680.000077411569
Missense (PolyPhen)175470.590.371884732
Synonymous0.005694854851.000.00003643504
Loss of Function8.44796.40.07260.000004791117

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000870.000087rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000390.000035rare
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Motor for anterograde axonal transport of synaptic vesicle precursors. {ECO:0000250}.;
Disease
DISEASE: Neuropathy, hereditary sensory, 2C (HSN2C) [MIM:614213]: A neurodegenerative disorder characterized by onset in the first decade of progressive distal sensory loss leading to ulceration and amputation of the fingers and toes. Affected individuals also develop distal muscle weakness, primarily affecting the lower limbs. {ECO:0000269|PubMed:21820098}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mental retardation, autosomal dominant 9 (MRD9) [MIM:614255]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:21376300, ECO:0000269|PubMed:25265257, ECO:0000269|PubMed:26125038, ECO:0000269|PubMed:26410750}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in KIF1A are a cause autosomal dominant spastic paraplegia. Spastic paraplegia is a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. {ECO:0000269|PubMed:25585697, ECO:0000269|PubMed:26410750}.;

Recessive Scores

pRec
0.152

Intolerance Scores

LoFtool
0.438
RVIS EVS
-3.67
RVIS percentile EVS
0.27

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.809

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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