Is CDC45 p.Met458Ile (c.1374G>C) pathogenic?

CDC45 p.Met458Ile (c.1374G>C) is classified Uncertain significance in CDC45 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-08). AlphaMissense: likely benign (0.0938); Absent from gnomAD v4.1.

How common is CDC45 p.Met458Ile (c.1374G>C) in the general population?

CDC45 p.Met458Ile (c.1374G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDC45 p.Met458Ile (c.1374G>C)?

AlphaMissense predicts likely benign (score 0.0938) — an in-silico prediction, not a clinical call.

CDC45 p.Met458Ile

c.1374G>C · rs1933702399 · VCV1010390

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0938 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0938	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -6.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.37	GERP -1.5
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.0069 · regional, not allelic
Overall
CADD	7.769	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

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: CDC45
Protein: p.Met458Ile
Coding: c.1374G>C
MANE Select: NM_003504
dbSNP: rs1933702399
Type: single nucleotide variant
Location: chr22:19514982 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.59 · 7 PDB
Residue 458: a UniProt-annotated variant site (in mgors7; likely pathogenic); an α-helix

Full CDC45 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDC45 p.Pro463Leu Pathogenic/Likely pathogenic ★★ ⚠ same type
CDC45 c.653+4C>T Uncertain significance ★★ same type
CDC45 p.Ala373Val Uncertain significance ★★ ⚠ same type
CDC45 p.Ala38Asp Uncertain significance ★★ ⚠ same type
CDC45 p.Arg157His Uncertain significance ★★ ⚠ same type
CDC45 p.Arg175Gln Uncertain significance ★★ ⚠ same type
CDC45 p.Arg251His Uncertain significance ★★ ⚠ same type
CDC45 p.Arg269Trp 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/cdc45-p-met458ile (accessed [today's date]).

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