KIF2A

Chr 5AD

kinesin family member 2A

Also known as: CDCBM3, HK2, KIF2

NCBI Gene: 3796 ENSG00000068796 UniProt: O00139 OMIM: 602591

The protein is a plus end-directed motor required for normal mitotic spindle activity and brain development. Autosomal dominant loss-of-function mutations cause cortical dysplasia with complex brain malformations. The high constraint against loss-of-function variants (pLI 0.99, LOEUF 0.16) reflects the protein's essential role in mitotic progression and neurodevelopment.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is a plus end-directed motor required for normal mitotic progression. The encoded protein is required for normal spindle activity during mitosis and is necessary for normal brain development. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

OMIM ResearchGenerating clinical summary…

DNmechanismADLOEUF 0.161 OMIM phenotype

Clinical Summary— KIF2A

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.16LOEUF

pLI 1.000

Z-score 5.48

OE 0.05 (0.02–0.16)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

4.04Z-score

OE missense 0.40 (0.35–0.46)

144 obs / 359.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.16)

0≤0.351.4

Missense OE?0.40 (0.35–0.46)

0≤0.61.4

Synonymous OE?0.82

0≤1.21.6

LoF obs/exp: 2 / 38.8Missense obs/exp: 144 / 359.3Syn Z: 1.54

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongKIF2A-related malformations of cortical development and microcephalyDNAD

This gene — mechanism propensity

0.4784th %ile

GOF

0.4579th %ile

LOF

0.69top 10%

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

LOFprediction above median · LOEUF 0.16

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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