MCPH1

Chr 8AR

microcephalin 1

Also known as: BRIT1, MCT

NCBI Gene: 79648 ENSG00000147316 UniProt: Q8NEM0 OMIM: 251200

The protein functions as a DNA damage response protein that maintains inhibitory phosphorylation of cyclin-dependent kinase 1 during G2/M checkpoint arrest. Mutations cause primary autosomal recessive microcephaly 1 and premature chromosome condensation syndrome, inherited in an autosomal recessive pattern. Loss of function leads to defective cell cycle checkpoint control, resulting in abnormal chromosome condensation and impaired brain development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a DNA damage response protein. The encoded protein may play a role in G2/M checkpoint arrest via maintenance of inhibitory phosphorylation of cyclin-dependent kinase 1. Mutations in this gene have been associated with primary autosomal recessive microcephaly 1 and premature chromosome condensation syndrome. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Microcephaly 1, primary, autosomal recessiveMIM #251200

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

1.44

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.44LOEUF

pLI 0.000

Z-score -0.65

OE 1.11 (0.87–1.44)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-4.76Z-score

OE missense 1.63 (1.53–1.73)

736 obs / 451.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.11 (0.87–1.44)

0≤0.351.4

Missense OE?1.63 (1.53–1.73)

0≤0.61.4

Synonymous OE?1.56

0≤1.21.6

LoF obs/exp: 42 / 37.7Missense obs/exp: 736 / 451.4Syn Z: -5.87

Background carrier burden — how many people carry a rare variant somewhere in MCPH1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 21

1,892 rare PASS variants

Rare truncating (LoF)

1 in 200

284 rare PASS variants

Rare synonymous (reference)

1 in 65

640 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MCPH1. 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 32	1 in 280
South Asian	~43k	1 in 22	1 in 280
Remaining (unassigned)	~30k	1 in 19	1 in 150
European (Finnish)	~27k	1 in 190	1 in 980
Admixed American	~22k	1 in 26	1 in 390
African / African American	~21k	1 in 19	1 in 250
East Asian	~20k	1 in 24	1 in 210
Ashkenazi Jewish	~13k	1 in 110	1 in 550
Middle Eastern	~2,884	1 in 27	1 in 160

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 9 of 14 coding exons well covered in gnomAD exomes; exons 1, 4, 7, 10, 14 marginal. Genomes: all 14.? see exons ↓