Is MCM4 p.Asp511Asn (c.1531G>A) pathogenic?

MCM4 p.Asp511Asn (c.1531G>A) is classified Uncertain significance in MCM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-30). AlphaMissense: likely pathogenic (0.9505); Very rare (popmax 0.00445%, eas).

How common is MCM4 p.Asp511Asn (c.1531G>A) in the general population?

MCM4 p.Asp511Asn (c.1531G>A) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about MCM4 p.Asp511Asn (c.1531G>A)?

AlphaMissense predicts likely pathogenic (score 0.9505) — an in-silico prediction, not a clinical call.

MCM4 p.Asp511Asn

c.1531G>A · rs1474445101 · VCV2114362

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9505 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9505	likely pathogenic
REVEL	0.513	indeterminate
SaProt	LLR -12.90	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.4, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.03 · regional, not allelic
Overall
CADD	33.0	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 0.00445% East Asian · 2/44,896 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.00031% 5/1,613,988 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,448
Admixed American	0.00167%	59,992
African / African-American	0.00134%	74,884
South Asian	0.0011%	91,076

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.Asp511Asn
Coding: c.1531G>A
MANE Select: NM_182746
dbSNP: rs1474445101
Type: single nucleotide variant
Location: chr8:47970607 (GRCh38)
Gene constraint: LOEUF 0.806 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.25 · 28 PDB
Residue 511: the mcm c-terminal aaa(+) atpase domain; 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-asp511asn (accessed [today's date]).

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