KIF11

Chr 10AD

kinesin family member 11

Also known as: EG5, HKSP, KNSL1, MCLMR, TRIP5

NCBI Gene: 3832 ENSG00000138160 UniProt: P52732

This gene encodes a motor protein that belongs to the kinesin-like protein family. Members of this protein family are known to be involved in various kinds of spindle dynamics. The function of this gene product includes chromosome positioning, centrosome separation and establishing a bipolar spindle during cell mitosis. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual developmentMIM #152950

Active trials

Pathogenic / LP

572

ClinVar variants

Pubs (1 yr)

3.3

Missense Z· constrained

0.12

LOEUF· LoF intolerant

Clinical Summary— KIF11

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Gene-Disease Validity (ClinGen)

microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

89 Pathogenic / Likely Pathogenic· 200 VUS of 572 total submissions

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 6.43

OE 0.04 (0.01–0.12)

Highly constrained

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

Missense Constraint

3.27Z-score

OE missense 0.60 (0.54–0.66)

310 obs / 519.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.04 (0.01–0.12)

0≤0.351.4

Missense OE0.60 (0.54–0.66)

0≤0.61.4

Synonymous OE0.94

0≤1.21.6

LoF obs/exp: 2 / 52.1Missense obs/exp: 310 / 519.9Syn Z: 0.62

LOFGOF

Badonyi & Marsh 2024 ↗

0.6065th %ile

GOF

0.6639th %ile

LOF

0.55top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 49% of P/LP variants are LoF · LOEUF 0.12

GOFprediction above median

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.

Literature Evidence

LOFIn addition to point mutations, KIF11 haploinsufficiency due to a deletion is causally associated with autosomal dominant microcephaly, chorioretinopathy and mild intellectual disability.PMID:31428438

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