Is MCM4 p.Ala616Val (c.1847C>T) pathogenic?

MCM4 p.Ala616Val (c.1847C>T) is classified Uncertain significance in MCM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-08). AlphaMissense: likely pathogenic (0.9729); Absent from gnomAD v4.1.

How common is MCM4 p.Ala616Val (c.1847C>T) in the general population?

MCM4 p.Ala616Val (c.1847C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MCM4 p.Ala616Val (c.1847C>T)?

AlphaMissense predicts likely pathogenic (score 0.9729) — an in-silico prediction, not a clinical call.

MCM4 p.Ala616Val

c.1847C>T · rs2551884794 · VCV2843944

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9729 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9729	likely pathogenic
REVEL	0.636	indeterminate
SaProt	LLR -11.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.24	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 1.5, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.03 · regional, not allelic
Overall
CADD	27.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MCM4
Protein: p.Ala616Val
Coding: c.1847C>T
MANE Select: NM_182746
dbSNP: rs2551884794
Type: single nucleotide variant
Location: chr8:47971387 (GRCh38)
Gene constraint: LOEUF 0.806 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.25 · 28 PDB
Residue 616: a β-strand; the mcm c-terminal aaa(+) atpase domain

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-ala616val (accessed [today's date]).

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