Is MCM3AP p.Pro528Arg (c.1583C>G) pathogenic?

MCM3AP p.Pro528Arg (c.1583C>G) is classified Uncertain significance in MCM3AP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-18). AlphaMissense: likely benign (0.0703); Very rare (popmax 0.000508%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MCM3AP p.Pro528Arg (c.1583C>G)?

MCM3AP p.Pro528Arg (c.1583C>G) is associated with Inborn genetic diseases (ClinVar).

How common is MCM3AP p.Pro528Arg (c.1583C>G) in the general population?

MCM3AP p.Pro528Arg (c.1583C>G) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about MCM3AP p.Pro528Arg (c.1583C>G)?

AlphaMissense predicts likely benign (score 0.0703) — an in-silico prediction, not a clinical call.

MCM3AP p.Pro528Arg

c.1583C>G · VCV4052648

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0703 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0703	likely benign
REVEL	0.004	strongly benign-leaning
SaProt	LLR -6.38	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 -0.47	GERP -1.9
Regional constraint	o/e 1.12	unconstrained · MANE · 7,693 bp · p 0.002 · regional, not allelic
Overall
CADD	0.373	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 0.000508% European (non-Finnish) · 6/1,180,008 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,614,120 alleles · very rare exomes 6/1,461,854 · genomes 0/152,266 · joint denominator

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: MCM3AP
Protein: p.Pro528Arg
Coding: c.1583C>G
MANE Select: NM_003906
Type: single nucleotide variant
Location: chr21:46280077 (GRCh38)
Gene constraint: LOEUF 0.769 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.83 · 7 PDB
Residue 528: the 'disordered' region

Full MCM3AP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MCM3AP p.Pro528Leu Uncertain significance ★ ⚠ same residue
MCM3AP p.Pro528Ser Uncertain significance ★ ⚠ same residue
MCM3AP p.Pro528= Likely benign ★ same residue
MCM3AP p.Ala1102Ser Uncertain significance ★★ ⚠ same condition
MCM3AP p.Ala1117Val Uncertain significance ★★ ⚠ same condition
MCM3AP p.Ala1283Thr Uncertain significance ★★ ⚠ same condition
MCM3AP p.Ala172Ser Uncertain significance ★★ ⚠ same condition
MCM3AP p.Ala17Gly Uncertain significance ★★ ⚠ 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/mcm3ap-p-pro528arg (accessed [today's date]).

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