Is MCM4 p.Arg795His (c.2384G>A) pathogenic?

MCM4 p.Arg795His (c.2384G>A) is classified Uncertain significance in MCM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-24). AlphaMissense: ambiguous (0.435); Ultra-rare (popmax 0.0116%, eas).

How common is MCM4 p.Arg795His (c.2384G>A) in the general population?

MCM4 p.Arg795His (c.2384G>A) is ultra-rare (popmax 0.0116%, eas) (gnomAD).

What do computational predictors say about MCM4 p.Arg795His (c.2384G>A)?

AlphaMissense predicts ambiguous (score 0.435) — an in-silico prediction, not a clinical call.

MCM4 p.Arg795His

c.2384G>A · rs146034877 · VCV1482118

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.435 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0116%, eas)

Computational evidence

Protein change
AlphaMissense	0.435	ambiguous
REVEL	0.624	indeterminate
SaProt	LLR -9.26	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 3,808 bp · p 0.82 · regional, not allelic
Overall
CADD	34.0	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 0.0116% East Asian · 5/43,158 alleles

Filtering AF 0.00449% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00363% 57/1,572,034 alleles · ultra-rare exomes 52/1,419,970 · genomes 5/152,064 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0116%	8,632
African / African-American	0.00415%	24,125
European (non-Finnish)	0.00395%	25,344
South Asian	0.00244%	41,005
Remaining individualsnot grpmax-eligible	0.00164%	60,836

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: MCM4
Protein: p.Arg795His
Coding: c.2384G>A
MANE Select: NM_182746
dbSNP: rs146034877
Type: single nucleotide variant
Location: chr8:47975733 (GRCh38)
Gene constraint: LOEUF 0.806 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.25 · 28 PDB
Residue 795: an α-helix

Full MCM4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MCM4 c.71-2A>G Pathogenic ★★ same type
MCM4 c.-74C>T Uncertain significance ★★ same type
MCM4 c.*56G>A Uncertain significance ★★ same type
MCM4 p.Ala141Gly Uncertain significance ★★ ⚠ same type
MCM4 p.Ala436Thr Uncertain significance ★★ ⚠ same type
MCM4 p.Ala668Thr Uncertain significance ★★ ⚠ same type
MCM4 p.Ala685Val Uncertain significance ★★ ⚠ same type
MCM4 p.Ala694Thr 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/mcm4-p-arg795his (accessed [today's date]).

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