CENPE

Chr 4AR

centromere protein E

Also known as: CENP-E, KIF10, MCPH13, PPP1R61

NCBI Gene: 1062 ENSG00000138778 UniProt: Q02224

Centrosome-associated protein E (CENPE) is a kinesin-like motor protein that accumulates in the G2 phase of the cell cycle. Unlike other centrosome-associated proteins, it is not present during interphase and first appears at the centromere region of chromosomes during prometaphase. This protein is required for stable spindle microtubule capture at kinetochores which is a necessary step in chromosome alignment during prometaphase. This protein also couples chromosome position to microtubule depolymerizing activity. Alternative splicing results in multiple transcript variants encoding distinct protein isoforms. [provided by RefSeq, Nov 2014]

Primary Disease Associations & Inheritance

?Microcephaly 13, primary, autosomal recessiveMIM #616051

Active trials

Pathogenic / LP

470

ClinVar variants

Pubs (1 yr)

1.3

Missense Z

0.31

LOEUF· LoF intolerant

Clinical Summary— CENPE

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Gene-Disease Validity (ClinGen)

autosomal recessive primary microcephaly · ARLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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ClinVar Variants

19 Pathogenic / Likely Pathogenic· 307 VUS of 470 total submissions

Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.31LOEUF

pLI 0.241

Z-score 8.44

OE 0.23 (0.17–0.31)

Highly constrained

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

Missense Constraint

1.27Z-score

OE missense 0.90 (0.85–0.94)

1113 obs / 1238.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.23 (0.17–0.31)

0≤0.351.4

Missense OE0.90 (0.85–0.94)

0≤0.61.4

Synonymous OE1.04

0≤1.21.6

LoF obs/exp: 32 / 139.6Missense obs/exp: 1113 / 1238.3Syn Z: -0.64

LOFDN

Badonyi & Marsh 2024 ↗

0.6744th %ile

GOF

0.6346th %ile

LOF

0.3259th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative 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.

LOF16% of P/LP variants are LoF · LOEUF 0.31

DNprediction 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.

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