Is MCPH1 p.Phe43Ser (c.128T>C) pathogenic?

MCPH1 p.Phe43Ser (c.128T>C) is classified Conflicting classifications of pathogenicity in MCPH1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2016-08-29). AlphaMissense: likely pathogenic (0.9685); Very rare (popmax 0.00212%, nfe); Associated with microcephaly 1, primary, autosomal recessive.

What condition is associated with MCPH1 p.Phe43Ser (c.128T>C)?

MCPH1 p.Phe43Ser (c.128T>C) is associated with microcephaly 1, primary, autosomal recessive (ClinVar).

How common is MCPH1 p.Phe43Ser (c.128T>C) in the general population?

MCPH1 p.Phe43Ser (c.128T>C) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about MCPH1 p.Phe43Ser (c.128T>C)?

AlphaMissense predicts likely pathogenic (score 0.9685) — an in-silico prediction, not a clinical call.

MCPH1 p.Phe43Ser

c.128T>C · rs587783733 · VCV158819

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9685 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcephaly 1, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.9685	likely pathogenic · top 2% in MCPH1
REVEL	0.918	moderately pathogenic-leaning
SaProt	LLR -10.84	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.49	unconstrained · MANE · 236 kb · p 2.4e-54 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00212% European (non-Finnish) · 25/1,179,832 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00171% 25/1,461,536 alleles · very rare

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.Phe43Ser
Coding: c.128T>C
MANE Select: NM_024596
dbSNP: rs587783733
Type: single nucleotide variant
Location: chr8:6414778 (GRCh38)
Gene constraint: LOEUF 1.342 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 9 PDB
Residue 43: the brct 1 domain

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-phe43ser (accessed [today's date]).

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