Is CDC45 p.Ser555Arg (c.1665C>A) pathogenic?

CDC45 p.Ser555Arg (c.1665C>A) is classified Uncertain significance in CDC45 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-01). AlphaMissense: likely pathogenic (0.6122); Very rare (popmax 0.0028%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CDC45 p.Ser555Arg (c.1665C>A)?

CDC45 p.Ser555Arg (c.1665C>A) is associated with Inborn genetic diseases (ClinVar).

How common is CDC45 p.Ser555Arg (c.1665C>A) in the general population?

CDC45 p.Ser555Arg (c.1665C>A) is very rare (popmax 0.0028%, nfe) (gnomAD).

What do computational predictors say about CDC45 p.Ser555Arg (c.1665C>A)?

AlphaMissense predicts likely pathogenic (score 0.6122) — an in-silico prediction, not a clinical call.

CDC45 p.Ser555Arg

c.1665C>A · VCV3488469

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6122 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6122	likely pathogenic
REVEL	0.245	benign-leaning
SaProt	LLR -7.88	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.56 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4	GERP 1.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.0069 · regional, not allelic
Overall
CADD	23.3	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 0.0028% European (non-Finnish) · 33/1,179,984 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00175%

Overall 0.00211% 34/1,613,972 alleles · very rare exomes 31/1,461,800 · genomes 3/152,172 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0028%	35,757
African / African-American	0.00133%	74,924

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.Ser555Arg
Coding: c.1665C>A
MANE Select: NM_003504
Type: single nucleotide variant
Location: chr22:19518872 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.59 · 7 PDB
Residue 555: 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

Disease context

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

Similar variants

CDC45 c.653+4C>T Uncertain significance ★★ same condition
CDC45 p.Ala373Val Uncertain significance ★★ ⚠ same condition
CDC45 p.Ala38Asp Uncertain significance ★★ ⚠ same condition
CDC45 p.Arg157His Uncertain significance ★★ ⚠ same condition
CDC45 p.Arg175Gln Uncertain significance ★★ ⚠ same condition
CDC45 p.Arg251His Uncertain significance ★★ ⚠ same condition
CDC45 p.Arg277Cys Uncertain significance ★★ ⚠ same condition
CDC45 p.Arg484Trp 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/cdc45-p-ser555arg (accessed [today's date]).

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