Is MCM4 p.Pro816Arg (c.2447C>G) pathogenic?

MCM4 p.Pro816Arg (c.2447C>G) is classified Uncertain significance in MCM4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-26). AlphaMissense: ambiguous (0.4006); Ultra-rare (popmax 0.0639%, amr).

How common is MCM4 p.Pro816Arg (c.2447C>G) in the general population?

MCM4 p.Pro816Arg (c.2447C>G) is ultra-rare (popmax 0.0639%, amr) (gnomAD).

What do computational predictors say about MCM4 p.Pro816Arg (c.2447C>G)?

AlphaMissense predicts ambiguous (score 0.4006) — an in-silico prediction, not a clinical call.

MCM4 p.Pro816Arg

c.2447C>G · rs562830599 · VCV1436632

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4006 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0639%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4006	ambiguous
REVEL	0.273	benign-leaning
SaProt	LLR -4.94	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 3,808 bp · p 0.82 · regional, not allelic
Overall
CADD	22.9	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 0.0639% Admixed American · 35/54,746 alleles

Filtering AF 0.0472% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0415%

Overall 0.00309% 49/1,586,560 alleles · ultra-rare exomes 41/1,434,300 · genomes 8/152,260 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0639%	1,564
Remaining individualsnot grpmax-eligible	0.00651%	15,352
African / African-American	0.00272%	36,802
European (non-Finnish)	0.000684%	146,190

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.Pro816Arg
Coding: c.2447C>G
MANE Select: NM_182746
dbSNP: rs562830599
Type: single nucleotide variant
Location: chr8:47975796 (GRCh38)
Gene constraint: LOEUF 0.806 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.25 · 28 PDB
Residue 816: a β-strand

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

Similar variants

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
MCM4 p.Ala694Thr 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-pro816arg (accessed [today's date]).

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