Is MCM4 p.Gln822Pro (c.2465A>C) pathogenic?

MCM4 p.Gln822Pro (c.2465A>C) is classified Uncertain significance in MCM4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-10). AlphaMissense: likely benign (0.2432); Ultra-rare (popmax 0.0166%, mid).

How common is MCM4 p.Gln822Pro (c.2465A>C) in the general population?

MCM4 p.Gln822Pro (c.2465A>C) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about MCM4 p.Gln822Pro (c.2465A>C)?

AlphaMissense predicts likely benign (score 0.2432) — an in-silico prediction, not a clinical call.

MCM4 p.Gln822Pro

c.2465A>C · rs767461218 · VCV1348812

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2432 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2432	likely benign
REVEL	0.288	benign-leaning
SaProt	LLR -9.01	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 3,808 bp · p 0.82 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0166% Middle Eastern · 1/6,042 alleles

Filtering AF 0.0025% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00219%

Overall 0.00259% 41/1,585,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,042
European (non-Finnish)	0.00333%	29,989
Remaining individualsnot grpmax-eligible	0.00163%	61,284

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.Gln822Pro
Coding: c.2465A>C
MANE Select: NM_182746
dbSNP: rs767461218
Type: single nucleotide variant
Location: chr8:47975814 (GRCh38)
Gene constraint: LOEUF 0.806 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.25 · 28 PDB
Residue 822: an α-helix

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

Similar variants

MCM4 p.Gln822Ter 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-gln822pro (accessed [today's date]).

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