Is MCM2 p.Arg18Pro (c.53G>C) pathogenic?

MCM2 p.Arg18Pro (c.53G>C) is classified Benign/Likely benign in MCM2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-01-10). AlphaMissense: likely benign (0.0885); Rare (popmax 0.887%, eas); Associated with autosomal dominant nonsyndromic hearing loss 70.

What condition is associated with MCM2 p.Arg18Pro (c.53G>C)?

MCM2 p.Arg18Pro (c.53G>C) is associated with autosomal dominant nonsyndromic hearing loss 70 (ClinVar).

How common is MCM2 p.Arg18Pro (c.53G>C) in the general population?

MCM2 p.Arg18Pro (c.53G>C) is rare (popmax 0.887%, eas) (gnomAD).

What do computational predictors say about MCM2 p.Arg18Pro (c.53G>C)?

AlphaMissense predicts likely benign (score 0.0885) — an in-silico prediction, not a clinical call.

MCM2 p.Arg18Pro

c.53G>C · rs185298481 · VCV2506305

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0885 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.887%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nonsyndromic hearing loss 70

Computational evidence

Protein change
AlphaMissense	0.0885	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -7.58	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 3	GERP -1.4, phastCons 0.2
Regional constraint	o/e 0.98	unconstrained · MANE · 6,632 bp · p 0.67 · regional, not allelic
Overall
CADD	19.28	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 0.887% East Asian · 398/44,876 alleles

Filtering AF 0.815% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.787%

Overall 0.026% 420/1,614,108 alleles · rare exomes 393/1,461,824 · genomes 27/152,284 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.887%	113
Remaining individualsnot grpmax-eligible	0.0208%	4,808
Admixed American	0.00833%	12,006
South Asian	0.0022%	45,543
African / African-American	0.00133%	75,032
European (non-Finnish)	8.47e-05%	1,180,011

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.Arg18Pro
Coding: c.53G>C
MANE Select: NM_004526
dbSNP: rs185298481
Type: single nucleotide variant
Location: chr3:127599364 (GRCh38)
Gene constraint: LOEUF 0.706 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.54 · 39 PDB
Residue 18: the 'disordered' region; the 'interaction with kat7' region

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.Arg18Trp Uncertain significance ★ ⚠ same residue
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.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-arg18pro (accessed [today's date]).

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