Is MCM2 p.Pro483Ser (c.1447C>T) pathogenic?

MCM2 p.Pro483Ser (c.1447C>T) is classified Uncertain significance in MCM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-03-01). AlphaMissense: likely pathogenic (0.9212); Ultra-rare (popmax 0.0285%, sas); Associated with autosomal dominant nonsyndromic hearing loss 70.

What condition is associated with MCM2 p.Pro483Ser (c.1447C>T)?

MCM2 p.Pro483Ser (c.1447C>T) is associated with autosomal dominant nonsyndromic hearing loss 70 (ClinVar).

How common is MCM2 p.Pro483Ser (c.1447C>T) in the general population?

MCM2 p.Pro483Ser (c.1447C>T) is ultra-rare (popmax 0.0285%, sas) (gnomAD).

What do computational predictors say about MCM2 p.Pro483Ser (c.1447C>T)?

AlphaMissense predicts likely pathogenic (score 0.9212) — an in-silico prediction, not a clinical call.

MCM2 p.Pro483Ser

c.1447C>T · rs767616299 · VCV1032223

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9212 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0285%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

autosomal dominant nonsyndromic hearing loss 70

Computational evidence

Protein change
AlphaMissense	0.9212	likely pathogenic
REVEL	0.463	indeterminate
SaProt	LLR -14.01	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 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 12 kb · p 1.6e-06 · regional, not allelic
Overall
CADD	29.0	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 0.0285% South Asian · 26/91,072 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0171%

Overall 0.00204% 33/1,614,014 alleles · ultra-rare exomes 33/1,461,726 · genomes 0/152,288 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0285%	3,503
Remaining individualsnot grpmax-eligible	0.0016%	62,502
African / African-American	0.00133%	75,034
European (non-Finnish)	0.000424%	235,986

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.Pro483Ser
Coding: c.1447C>T
MANE Select: NM_004526
dbSNP: rs767616299
Type: single nucleotide variant
Location: chr3:127615880 (GRCh38)
Gene constraint: LOEUF 0.706 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.54 · 39 PDB
Residue 483: the mcm c-terminal aaa(+) atpase domain; a β-strand

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

Disease context

autosomal dominant nonsyndromic hearing loss 70 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MCM2 p.Arg284Cys Uncertain significance ★★ ⚠ same condition
MCM2 p.Arg562Trp Uncertain significance ★★ ⚠ same condition
MCM2 p.Arg815His Uncertain significance ★★ ⚠ same condition
MCM2 p.Pro504Thr Uncertain significance ★★ ⚠ same condition
MCM2 c.2013+10A>G Benign ★★ same condition
MCM2 p.Arg18Pro Benign/Likely benign ★★ same condition
MCM2 p.Ile168= Benign ★★ same condition
MCM2 p.Lys150Arg Likely benign ★★ same condition

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-pro483ser (accessed [today's date]).

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