Is MCM2 p.Pro338Ser (c.1012C>T) pathogenic?

MCM2 p.Pro338Ser (c.1012C>T) is classified Uncertain significance in MCM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-19). AlphaMissense: likely pathogenic (0.9633); Very rare (popmax 0.00223%, eas).

How common is MCM2 p.Pro338Ser (c.1012C>T) in the general population?

MCM2 p.Pro338Ser (c.1012C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about MCM2 p.Pro338Ser (c.1012C>T)?

AlphaMissense predicts likely pathogenic (score 0.9633) — an in-silico prediction, not a clinical call.

MCM2 p.Pro338Ser

c.1012C>T · rs763930660 · VCV1932877

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9633 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9633	likely pathogenic
REVEL	0.428	indeterminate
SaProt	LLR -13.73	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 12 kb · p 1.6e-06 · regional, not allelic
Overall
CADD	26.7	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 0.00223% East Asian · 1/44,892 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000248% 4/1,614,130 alleles · very rare exomes 3/1,461,886 · genomes 1/152,244 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,892
South Asian	0.0022%	45,546
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: MCM2
Protein: p.Pro338Ser
Coding: c.1012C>T
MANE Select: NM_004526
dbSNP: rs763930660
Type: single nucleotide variant
Location: chr3:127606728 (GRCh38)
Gene constraint: LOEUF 0.706 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.54 · 39 PDB
Residue 338: a β-strand

Full MCM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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MCM2 p.Arg126Gln Uncertain significance ★★ ⚠ same type
MCM2 p.Arg149His Uncertain significance ★★ ⚠ same type
MCM2 p.Arg152His Uncertain significance ★★ ⚠ same type
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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/mcm2-p-pro338ser (accessed [today's date]).

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