Is MCM4 p.Arg330Cys (c.988C>T) pathogenic?

MCM4 p.Arg330Cys (c.988C>T) is classified Uncertain significance in MCM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-20). AlphaMissense: likely benign (0.0947); Ultra-rare (popmax 0.0386%, afr).

How common is MCM4 p.Arg330Cys (c.988C>T) in the general population?

MCM4 p.Arg330Cys (c.988C>T) is ultra-rare (popmax 0.0386%, afr) (gnomAD).

What do computational predictors say about MCM4 p.Arg330Cys (c.988C>T)?

AlphaMissense predicts likely benign (score 0.0947) — an in-silico prediction, not a clinical call.

MCM4 p.Arg330Cys

c.988C>T · rs144766420 · VCV1448378

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0947 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0386%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0947	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -11.70	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP -0.59, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.03 · regional, not allelic
Overall
CADD	25.0	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 0.0386% African / African-American · 29/75,052 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0238%

Overall 0.00248% 40/1,613,906 alleles · ultra-rare exomes 23/1,461,582 · genomes 17/152,324 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0386%	2,588
East Asian	0.00669%	14,953
Remaining individualsnot grpmax-eligible	0.0032%	31,249
Admixed American	0.00167%	60,022
European (non-Finnish)	0.000424%	236,004

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.Arg330Cys
Coding: c.988C>T
MANE Select: NM_182746
dbSNP: rs144766420
Type: single nucleotide variant
Location: chr8:47966342 (GRCh38)
Gene constraint: LOEUF 0.806 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.25 · 28 PDB
Residue 330: a turn

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

Similar variants

MCM4 p.Arg330His 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-arg330cys (accessed [today's date]).

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