Is MCM4 p.Ser228Phe (c.683C>T) pathogenic?

MCM4 p.Ser228Phe (c.683C>T) is classified Uncertain significance in MCM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-13). AlphaMissense: likely benign (0.11); Ultra-rare (popmax 0.0122%, afr).

How common is MCM4 p.Ser228Phe (c.683C>T) in the general population?

MCM4 p.Ser228Phe (c.683C>T) is ultra-rare (popmax 0.0122%, afr) (gnomAD).

What do computational predictors say about MCM4 p.Ser228Phe (c.683C>T)?

AlphaMissense predicts likely benign (score 0.11) — an in-silico prediction, not a clinical call.

MCM4 p.Ser228Phe

c.683C>T · rs764079802 · VCV2785383

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.11 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.11	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -10.29	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -1.8, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.03 · regional, not allelic
Overall
CADD	20.8	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 0.0122% African / African-American · 9/73,754 alleles

Filtering AF 0.00632% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00474%

Overall 0.000567% 9/1,587,736 alleles · ultra-rare exomes 4/1,435,520 · genomes 5/152,216 · joint denominator

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: MCM4
Protein: p.Ser228Phe
Coding: c.683C>T
MANE Select: NM_182746
dbSNP: rs764079802
Type: single nucleotide variant
Location: chr8:47963030 (GRCh38)
Gene constraint: LOEUF 0.806 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.25 · 28 PDB
Residue 228: an α-helix

Full MCM4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MCM4 p.Ser228Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
MCM4 p.Ser228= Likely benign ★ same residue
MCM4 c.71-2A>G Pathogenic ★★ same type
MCM4 c.-74C>T Uncertain significance ★★ same type
MCM4 c.*56G>A Uncertain significance ★★ same type
MCM4 p.Ala141Gly Uncertain significance ★★ ⚠ same type
MCM4 p.Ala436Thr Uncertain significance ★★ ⚠ same type
MCM4 p.Ala668Thr Uncertain significance ★★ ⚠ same type

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/mcm4-p-ser228phe (accessed [today's date]).

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