Is MCPH1 p.Ser742= (c.2226C>T) pathogenic?

MCPH1 p.Ser742= (c.2226C>T) is classified Benign in MCPH1 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-04-28). Common (popmax 68%, eas) — too common for a highly-penetrant pathogenic allele; Associated with microcephaly 1, primary, autosomal recessive.

What condition is associated with MCPH1 p.Ser742= (c.2226C>T)?

MCPH1 p.Ser742= (c.2226C>T) is associated with microcephaly 1, primary, autosomal recessive (ClinVar).

MCPH1 p.Ser742=

Q: How common is MCPH1 p.Ser742= (c.2226C>T) in the general population?

MCPH1 p.Ser742= (c.2226C>T) is common (popmax 68%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2226C>T · rs2912010 · VCV158844

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Common

common (popmax 68%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

microcephaly 1, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.77	GERP -4.1
Overall
CADD	2.228	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 68% East Asian · 30,516/44,862 alleles

Filtering AF 67.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 67.1%

Overall 41.1% 662,110/1,609,454 alleles · common exomes 600,865/1,457,434 · genomes 61,245/152,020 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	68%	1
South Asian	49.3%	2
Finnishnot grpmax-eligible	44.4%	2
Remaining individualsnot grpmax-eligible	40.6%	2
Middle Eastern	40.2%	2
European (non-Finnish)	40%	3
Admixed American	38.6%	3
African / African-American	36.5%	3
Ashkenazi Jewishnot grpmax-eligible	33.2%	3
Amishnot grpmax-eligible	32.6%	3

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MCPH1
Protein: p.Ser742=
Coding: c.2226C>T
MANE Select: NM_024596
dbSNP: rs2912010
Type: single nucleotide variant
Location: chr8:6621465 (GRCh38)

Full MCPH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcephaly 1, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mcph1-p-ser742 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown