Is CDC45 p.Arg174Trp (c.520C>T) pathogenic?

CDC45 p.Arg174Trp (c.520C>T) is classified Conflicting classifications of pathogenicity in CDC45 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-29). AlphaMissense: likely benign (0.1321); Rare (popmax 0.202%, amr).

How common is CDC45 p.Arg174Trp (c.520C>T) in the general population?

CDC45 p.Arg174Trp (c.520C>T) is rare (popmax 0.202%, amr) (gnomAD).

What do computational predictors say about CDC45 p.Arg174Trp (c.520C>T)?

AlphaMissense predicts likely benign (score 0.1321) — an in-silico prediction, not a clinical call.

CDC45 p.Arg174Trp

c.520C>T · rs184924520 · VCV1003669

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1321 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.202%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1321	likely benign
REVEL	0.214	benign-leaning
SaProt	LLR -11.48	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.8	GERP -0.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.0069 · regional, not allelic
Overall
CADD	23.5	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 0.202% Admixed American · 121/60,008 alleles

Filtering AF 0.172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.161%

Overall 0.00862% 139/1,613,252 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.202%	496
East Asian	0.00668%	14,962
Remaining individualsnot grpmax-eligible	0.00641%	15,605
South Asian	0.0022%	45,513
Finnishnot grpmax-eligible	0.00156%	64,026
African / African-American	0.00133%	74,998
European (non-Finnish)	0.000593%	168,568

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: CDC45
Protein: p.Arg174Trp
Coding: c.520C>T
MANE Select: NM_003504
dbSNP: rs184924520
Type: single nucleotide variant
Location: chr22:19494360 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.59 · 7 PDB
Residue 174: 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-arg174trp (accessed [today's date]).

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