Is MCM4 p.Pro176Arg (c.527C>G) pathogenic?

MCM4 p.Pro176Arg (c.527C>G) is classified Uncertain significance in MCM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-08). AlphaMissense: likely benign (0.1618); Absent from gnomAD v4.1.

How common is MCM4 p.Pro176Arg (c.527C>G) in the general population?

MCM4 p.Pro176Arg (c.527C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MCM4 p.Pro176Arg (c.527C>G)?

AlphaMissense predicts likely benign (score 0.1618) — an in-silico prediction, not a clinical call.

MCM4 p.Pro176Arg

c.527C>G · rs761162193 · VCV2701893

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1618 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1618	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -10.21	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 3.2	GERP 1.3, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.03 · regional, not allelic
Overall
CADD	21.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MCM4
Protein: p.Pro176Arg
Coding: c.527C>G
MANE Select: NM_182746
dbSNP: rs761162193
Type: single nucleotide variant
Location: chr8:47962789 (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 p.Pro176Thr Uncertain significance ★★ ⚠ same residue
MCM4 p.Pro176Leu Uncertain significance ★ ⚠ same residue
MCM4 p.Pro176Ser 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

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-pro176arg (accessed [today's date]).

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