Is MCM4 p.Pro191Ser (c.571C>T) pathogenic?

MCM4 p.Pro191Ser (c.571C>T) is classified Likely benign in MCM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-26). AlphaMissense: ambiguous (0.3861); Ultra-rare (popmax 0.0647%, eas).

How common is MCM4 p.Pro191Ser (c.571C>T) in the general population?

MCM4 p.Pro191Ser (c.571C>T) is ultra-rare (popmax 0.0647%, eas) (gnomAD).

What do computational predictors say about MCM4 p.Pro191Ser (c.571C>T)?

AlphaMissense predicts ambiguous (score 0.3861) — an in-silico prediction, not a clinical call.

MCM4 p.Pro191Ser

c.571C>T · rs548816846 · VCV2720340

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3861 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0647%, eas)

Computational evidence

Protein change
AlphaMissense	0.3861	ambiguous
REVEL	0.371	indeterminate
SaProt	LLR -12.30	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.03 · regional, not allelic
Overall
CADD	24.7	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 0.0647% East Asian · 29/44,810 alleles

Filtering AF 0.0462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.04%

Overall 0.00224% 36/1,608,172 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0647%	1,545
Remaining individualsnot grpmax-eligible	0.00642%	15,567
African / African-American	0.00134%	74,690
European (non-Finnish)	0.00017%	589,098

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.Pro191Ser
Coding: c.571C>T
MANE Select: NM_182746
dbSNP: rs548816846
Type: single nucleotide variant
Location: chr8:47962833 (GRCh38)
Gene constraint: LOEUF 0.806 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.25 · 28 PDB

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

Similar variants

MCM4 p.Pro191Thr Uncertain significance ★ 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
MCM4 p.Ala685Val 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-pro191ser (accessed [today's date]).

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