KIF5C

Chr 2

kinesin family member 5C

Also known as: CDCBM2, KINN, NKHC, NKHC-2, NKHC2

NCBI Gene: 3800 ENSG00000168280 UniProt: O60282

KIF5C encodes a kinesin heavy chain that transports cargo along microtubules in the central nervous system and is involved in synaptic transmission, dendritic mRNA trafficking, and axonal transport. Mutations cause complex cortical dysplasia with other brain malformations through autosomal dominant inheritance. This gene is extremely intolerant to loss-of-function variants (pLI ~1.0), reflecting its critical role in neuronal function.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a kinesin heavy chain subunit involved in the transport of cargo within the central nervous system. The encoded protein, which acts as a tetramer by associating with another heavy chain and two light chains, interacts with protein kinase CK2. Mutations in this gene have been associated with complex cortical dysplasia with other brain malformations-2. Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Jul 2015]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.12

Clinical Summary— KIF5C

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Gene-Disease Validity (ClinGen)

complex cortical dysplasia with other brain malformations 2 · ADModerate

Moderate evidence — consider for supplementary testing

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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

10 unique Pathogenic / Likely Pathogenic· 105 VUS of 303 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.12LOEUF

pLI 1.000

Z-score 6.54

OE 0.04 (0.01–0.12)

Highly constrained

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

Missense Constraint?

4.05Z-score

OE missense 0.50 (0.45–0.55)

253 obs / 510.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.12)

0≤0.351.4

Missense OE?0.50 (0.45–0.55)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 2 / 53.7Missense obs/exp: 253 / 510.8Syn Z: 0.43

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongKIF5C-related cortical dysplasia, complex, with other brain malformationsOTHERAD

This gene — mechanism propensity

0.5870th %ile

GOF

0.4481th %ile

LOF

0.70top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 20% of P/LP variants are LoF · LOEUF 0.12

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

ClinVar Variant Classifications

303 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic9

VUS105

Likely Benign110

Benign66

Conflicting4

Pathogenic

Likely Pathogenic

105

VUS

110

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	2	7	0	0	9
VUS	7	89	7	2	105
Likely Benign	0	13	67	30	110
Benign	0	1	55	10	66
Conflicting	—				4
Total	9	111	129	42	295

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap KIF5C — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →