KNL1
Chr 15ARkinetochore scaffold 1
Also known as: AF15Q14, CASC5, CT29, D40, MCPH4, PPP1R55, Spc7, hKNL-1
The protein functions as a scaffold component of the outer kinetochore complex that mediates chromosome-microtubule attachments during cell division and recruits spindle assembly checkpoint proteins to ensure proper chromosome segregation. Mutations cause autosomal recessive primary microcephaly-4, a disorder characterized by severely reduced brain size present from birth. The gene shows high constraint against loss-of-function variants (LOEUF 0.314), indicating that complete loss of protein function is poorly tolerated.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Tolerant to missense variation
Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.
The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.
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
200 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 3 | 0 | 1 | 0 | 4 |
Likely Pathogenic | 6 | 1 | 0 | 0 | 7 |
VUS | 1 | 75 | 5 | 0 | 81 |
Likely Benign | 0 | 2 | 24 | 24 | 50 |
Benign | 0 | 0 | 29 | 0 | 29 |
| Total | 10 | 78 | 59 | 24 | 171 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
KNL1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools