Is MCM2 p.Pro191His (c.572C>A) pathogenic?

MCM2 p.Pro191His (c.572C>A) is classified Uncertain significance in MCM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-23). AlphaMissense: likely pathogenic (0.9915); Very rare (popmax 0.000508%, nfe).

How common is MCM2 p.Pro191His (c.572C>A) in the general population?

MCM2 p.Pro191His (c.572C>A) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about MCM2 p.Pro191His (c.572C>A)?

AlphaMissense predicts likely pathogenic (score 0.9915) — an in-silico prediction, not a clinical call.

MCM2 p.Pro191His

c.572C>A · VCV3544176

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9915 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9915	likely pathogenic
REVEL	0.342	indeterminate
SaProt	LLR -14.23	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 6,632 bp · p 0.67 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000508% European (non-Finnish) · 6/1,179,958 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,940 alleles · very rare exomes 6/1,461,654 · genomes 0/152,286 · 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: MCM2
Protein: p.Pro191His
Coding: c.572C>A
MANE Select: NM_004526
Type: single nucleotide variant
Location: chr3:127605055 (GRCh38)
Gene constraint: LOEUF 0.706 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.54 · 39 PDB
Residue 191: the 'interaction with kat7' region; an α-helix

Full MCM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MCM2 p.Pro191Ser Uncertain significance ★ ⚠ same residue
MCM2 p.Ala148Thr Uncertain significance ★★ ⚠ same type
MCM2 p.Ala2Glu Uncertain significance ★★ ⚠ same type
MCM2 p.Ala400Thr Uncertain significance ★★ ⚠ same type
MCM2 p.Arg126Gln Uncertain significance ★★ ⚠ same type
MCM2 p.Arg149His Uncertain significance ★★ ⚠ same type
MCM2 p.Arg152His Uncertain significance ★★ ⚠ same type
MCM2 p.Arg227His 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/mcm2-p-pro191his (accessed [today's date]).

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