Is MCM4 p.Ile783Val (c.2347A>G) pathogenic?

MCM4 p.Ile783Val (c.2347A>G) is classified Uncertain significance in MCM4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-19). AlphaMissense: likely benign (0.1317); Very rare (popmax 0.00335%, amr).

How common is MCM4 p.Ile783Val (c.2347A>G) in the general population?

MCM4 p.Ile783Val (c.2347A>G) is very rare (popmax 0.00335%, amr) (gnomAD).

What do computational predictors say about MCM4 p.Ile783Val (c.2347A>G)?

AlphaMissense predicts likely benign (score 0.1317) — an in-silico prediction, not a clinical call.

MCM4 p.Ile783Val

c.2347A>G · rs955851112 · VCV2550232

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1317 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00335%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1317	likely benign
REVEL	0.254	benign-leaning
SaProt	LLR -6.23	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.35	donor gain · deltas
Pangolin	Δ0.22	gain · loss 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.4	GERP 2.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 3,808 bp · p 0.82 · regional, not allelic
Overall
CADD	22.8	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 0.00335% Admixed American · 2/59,706 alleles

Filtering AF 0.000556% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000208%

Overall 0.000434% 7/1,612,476 alleles · very rare exomes 6/1,460,256 · genomes 1/152,220 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00335%	29,853
African / African-American	0.00134%	74,856
European (non-Finnish)	0.000339%	294,771

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.Ile783Val
Coding: c.2347A>G
MANE Select: NM_182746
dbSNP: rs955851112
Type: single nucleotide variant
Location: chr8:47974944 (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 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-ile783val (accessed [today's date]).

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