Is MCPH1 p.Phe476= (c.1428C>T) pathogenic?

MCPH1 p.Phe476= (c.1428C>T) is classified Benign in MCPH1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 41.6%, afr) — too common for a highly-penetrant pathogenic allele; Associated with microcephaly 1, primary, autosomal recessive.

What condition is associated with MCPH1 p.Phe476= (c.1428C>T)?

MCPH1 p.Phe476= (c.1428C>T) is associated with microcephaly 1, primary, autosomal recessive (ClinVar).

MCPH1 p.Phe476=

Q: How common is MCPH1 p.Phe476= (c.1428C>T) in the general population?

MCPH1 p.Phe476= (c.1428C>T) is common (popmax 41.6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1428C>T · rs2920676 · VCV96128

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 41.6%, afr) — 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 assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.63	GERP -3.3
Overall
CADD	0.629	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 41.6% African / African-American · 31,165/74,970 alleles

Filtering AF 41.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 41%

Overall 5.19% 83,800/1,614,124 alleles · common exomes 61,889/1,461,882 · genomes 21,911/152,242 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	41.6%	2
East Asian	15.6%	6
South Asian	14.9%	7
Middle Eastern	7.57%	13
Remaining individualsnot grpmax-eligible	6.87%	15
Admixed American	6.67%	15
Ashkenazi Jewishnot grpmax-eligible	3.64%	27
Finnishnot grpmax-eligible	3.6%	28
European (non-Finnish)	1.69%	59
Amishnot grpmax-eligible	0.11%	912

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.Phe476=
Coding: c.1428C>T
MANE Select: NM_024596
dbSNP: rs2920676
Type: single nucleotide variant
Location: chr8:6445150 (GRCh38)
Gene constraint: LOEUF 1.342 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 9 PDB

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

Similar variants

MCPH1 c.321+2T>C Likely pathogenic ★★ same condition
MCPH1 c.322-1G>C Pathogenic/Likely pathogenic ★★ same condition
MCPH1 p.Gln386Ter Pathogenic/Likely pathogenic ★★ same condition
MCPH1 p.Gly245Ter Pathogenic/Likely pathogenic ★★ same condition
MCPH1 p.Leu542Ter Pathogenic/Likely pathogenic ★★ same condition
MCPH1 p.Ser72Leu Pathogenic/Likely pathogenic ★★ same condition
MCPH1 c.1935+6T>C Uncertain significance ★★ same condition
MCPH1 p.Ala702Val Uncertain significance ★★ ⚠ same condition

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-phe476 (accessed [today's date]).

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