Is MCM5 p.Pro366Ser (c.1096C>T) pathogenic?

MCM5 p.Pro366Ser (c.1096C>T) is classified Uncertain significance in MCM5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely pathogenic (0.8271); Rare (popmax 0.186%, afr).

How common is MCM5 p.Pro366Ser (c.1096C>T) in the general population?

MCM5 p.Pro366Ser (c.1096C>T) is rare (popmax 0.186%, afr) (gnomAD).

What do computational predictors say about MCM5 p.Pro366Ser (c.1096C>T)?

AlphaMissense predicts likely pathogenic (score 0.8271) — an in-silico prediction, not a clinical call.

MCM5 p.Pro366Ser

c.1096C>T · rs139470681 · VCV1444897

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8271 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.186%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8271	likely pathogenic
REVEL	0.325	indeterminate
SaProt	LLR -8.56	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 13 kb · p 0.006 · regional, not allelic
Overall
CADD	28.4	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 0.186% African / African-American · 139/74,782 alleles

Filtering AF 0.161% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.151%

Overall 0.0093% 149/1,601,856 alleles · rare exomes 68/1,449,532 · genomes 81/152,324 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.186%	538
Remaining individualsnot grpmax-eligible	0.00483%	20,687
Admixed American	0.00333%	30,004
European (non-Finnish)	0.000428%	233,763

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: MCM5
Protein: p.Pro366Ser
Coding: c.1096C>T
MANE Select: NM_006739
dbSNP: rs139470681
Type: single nucleotide variant
Location: chr22:35413879 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.57 · 27 PDB
Residue 366: the mcm c-terminal aaa(+) atpase domain; a β-strand

Full MCM5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MCM5 p.Ala160Val Uncertain significance ★★ ⚠ same type
MCM5 p.Ala327Val Uncertain significance ★★ ⚠ same type
MCM5 p.Ala543Thr Uncertain significance ★★ ⚠ same type
MCM5 p.Ala620Thr Uncertain significance ★★ ⚠ same type
MCM5 p.Arg138His Uncertain significance ★★ ⚠ same type
MCM5 p.Arg167Cys Uncertain significance ★★ ⚠ same type
MCM5 p.Arg167His Uncertain significance ★★ ⚠ same type
MCM5 p.Arg176Cys 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/mcm5-p-pro366ser (accessed [today's date]).

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