MIS12

Chr 17

MIS12 kinetochore complex component

Also known as: 2510025F08Rik, KNTC2AP, MTW1, hMis12

NCBI Gene: 79003 ENSG00000167842 UniProt: Q9H081 OMIM: 609178

The MIS12 protein is essential for proper kinetochore formation and chromosome alignment during cell division, ensuring accurate chromosome segregation by facilitating spindle microtubule attachments to kinetochores. Mutations in MIS12 cause Mosaic variegated aneuploidy syndrome 4, an autosomal recessive disorder characterized by growth retardation, intellectual disability, microcephaly, and increased cancer risk due to chromosomal instability. This condition typically presents in early childhood with developmental delays and distinctive facial features.

OMIM ResearchSummary from RefSeq, UniProt

Involved in attachment of mitotic spindle microtubules to kinetochore and kinetochore assembly. Located in kinetochore and nucleus. Part of MIS12/MIND type complex. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.07

Clinical Summary— MIS12

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

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ClinVar Variants

22 VUS of 26 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.07LOEUF

pLI 0.147

Z-score 1.48

OE 0.34 (0.14–1.07)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.64Z-score

OE missense 0.83 (0.70–0.98)

90 obs / 108.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.14–1.07)

0≤0.351.4

Missense OE?0.83 (0.70–0.98)

0≤0.61.4

Synonymous OE?1.30

0≤1.21.6

LoF obs/exp: 2 / 5.9Missense obs/exp: 90 / 108.9Syn Z: -1.54

This gene — mechanism propensity

0.6648th %ile

GOF

0.5661th %ile

LOF

0.3162th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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.

ClinVar Variant Classifications

26 submitted variants in ClinVar

ClinVar

Classification Summary

VUS22

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	22	22
Likely Benign	0	0
Benign	0	0
Total	22	22

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap MIS12 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →