STIL

Chr 1AR

STIL centriolar assembly protein

Also known as: MCPH7, SIL

NCBI Gene: 6491 ENSG00000123473 UniProt: Q15468 OMIM: 181590

The protein regulates the mitotic spindle checkpoint by monitoring chromosome segregation during cell division and modulating Cdc2 kinase activity to ensure proper chromosome distribution to daughter cells. Biallelic mutations cause primary microcephaly 7, an autosomal recessive disorder characterized by reduced brain size. The pathogenic mechanism involves disrupted cell division control leading to impaired neuronal proliferation during brain development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a cytoplasmic protein implicated in regulation of the mitotic spindle checkpoint, a regulatory pathway that monitors chromosome segregation during cell division to ensure the proper distribution of chromosomes to daughter cells. The protein is phosphorylated in mitosis and in response to activation of the spindle checkpoint, and disappears when cells transition to G1 phase. It interacts with a mitotic regulator, and its expression is required to efficiently activate the spindle checkpoint. It is proposed to regulate Cdc2 kinase activity during spindle checkpoint arrest. Chromosomal deletions that fuse this gene and the adjacent locus commonly occur in T cell leukemias, and are thought to arise through illegitimate V-(D)-J recombination events. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Microcephaly 7, primary, autosomal recessiveMIM #612703

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · autosomal recessive primary microcephaly · AR · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.38

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.38LOEUF

pLI 0.201

Z-score 5.04

OE 0.24 (0.15–0.38)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.13Z-score

OE missense 0.88 (0.82–0.94)

587 obs / 668.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.24 (0.15–0.38)

0≤0.351.4

Missense OE?0.88 (0.82–0.94)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 12 / 50.8Missense obs/exp: 587 / 668.9Syn Z: 1.54

Background carrier burden — how many people carry a rare variant somewhere in STIL?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 44

1,481 rare PASS variants

Rare truncating (LoF)

1 in 2,000

120 rare PASS variants

Rare synonymous (reference)

1 in 140

501 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for STIL. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 63	1 in 2,300
South Asian	~43k	1 in 35	1 in 850
Remaining (unassigned)	~30k	1 in 37	1 in 3,400
European (Finnish)	~27k	1 in 110	1 in 3,300
Admixed American	~22k	1 in 52	1 in 3,200
African / African American	~21k	1 in 42	1 in 1,500
East Asian	~20k	1 in 49	1 in 1,200
Ashkenazi Jewish	~13k	1 in 120	none seen
Middle Eastern	~2,884	1 in 49	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 16 coding exons well covered in gnomAD exomes and genomes.? see exons ↓