KNL1

Chr 15AR

kinetochore scaffold 1

Also known as: AF15Q14, CASC5, CT29, D40, MCPH4, PPP1R55, Spc7, hKNL-1

NCBI Gene: 57082 ENSG00000137812 UniProt: Q8NG31 OMIM: 609173

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a component of the multiprotein assembly that is required for creation of kinetochore-microtubule attachments and chromosome segregation. The encoded protein functions as a scaffold for proteins that influence the spindle assembly checkpoint during the eukaryotic cell cycle and it interacts with at least five different kinetochore proteins and two checkpoint kinases. In adults, this gene is predominantly expressed in normal testes, various cancer cell lines and primary tumors from other tissues and is ubiquitously expressed in fetal tissues. This gene was originally identified as a fusion partner with the mixed-lineage leukemia (MLL) gene in t(11;15)(q23;q14). Mutations in this gene cause autosomal recessive primary microcephaly-4 (MCPH4). Alternative splicing results in multiple transcript variants encoding different isoforms. Additional splice variants have been described but their biological validity has not been confirmed. [provided by RefSeq, Jan 2013]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.311 OMIM phenotype

Clinical Summary— KNL1

⚡

Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.78) — some intolerance to loss-of-function variants.

📋

ClinVar Variants

22 unique Pathogenic / Likely Pathogenic· 181 VUS of 431 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.31LOEUF

pLI 0.783

Z-score 6.86

OE 0.21 (0.15–0.31)

Highly constrained

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

Missense Constraint?

-0.01Z-score

OE missense 1.00 (0.95–1.05)

1166 obs / 1165.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.21 (0.15–0.31)

0≤0.351.4

Missense OE?1.00 (0.95–1.05)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 19 / 88.8Missense obs/exp: 1166 / 1165.2Syn Z: 0.44

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongKNL1-related primary microcephalyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.4090th %ile

GOF

0.15100th %ile

LOF

0.65top 25%

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

431 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic17

VUS181

Likely Benign119

Benign51

Conflicting29

Pathogenic

Likely Pathogenic

181

VUS

119

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	1	0	0	5
Likely Pathogenic	14	2	0	1	17
VUS	4	147	17	13	181
Likely Benign	0	14	57	48	119
Benign	0	11	36	4	51
Conflicting	—				29
Total	22	175	110	66	402

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap KNL1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →