Is MCM4 p.Pro176Ser (c.526C>T) pathogenic?

MCM4 p.Pro176Ser (c.526C>T) is classified Uncertain significance in MCM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-27). AlphaMissense: likely benign (0.1301); Ultra-rare (popmax 0.0388%, afr).

How common is MCM4 p.Pro176Ser (c.526C>T) in the general population?

MCM4 p.Pro176Ser (c.526C>T) is ultra-rare (popmax 0.0388%, afr) (gnomAD).

What do computational predictors say about MCM4 p.Pro176Ser (c.526C>T)?

AlphaMissense predicts likely benign (score 0.1301) — an in-silico prediction, not a clinical call.

MCM4 p.Pro176Ser

c.526C>T · rs187841020 · VCV1486190

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1301 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0388%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1301	likely benign
REVEL	0.202	benign-leaning
SaProt	LLR -9.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.2, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.03 · regional, not allelic
Overall
CADD	18.59	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 0.0388% African / African-American · 29/74,668 alleles

Filtering AF 0.0278% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0239%

Overall 0.0023% 37/1,608,438 alleles · ultra-rare exomes 20/1,456,272 · genomes 17/152,166 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0388%	2,575
Ashkenazi Jewishnot grpmax-eligible	0.0034%	29,434
Remaining individualsnot grpmax-eligible	0.00321%	31,140
South Asian	0.00224%	44,664
Admixed American	0.0017%	58,816
European (non-Finnish)	0.00017%	589,119

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.Pro176Ser
Coding: c.526C>T
MANE Select: NM_182746
dbSNP: rs187841020
Type: single nucleotide variant
Location: chr8:47962788 (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.Pro176Arg Uncertain significance ★ ⚠ same residue
MCM4 p.Pro176Leu 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-pro176ser (accessed [today's date]).

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