Is CDC45 p.Phe351Cys (c.1052T>G) pathogenic?

CDC45 p.Phe351Cys (c.1052T>G) is classified Uncertain significance in CDC45 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-23). AlphaMissense: likely pathogenic (0.6516); Very rare (popmax 0.000257%, nfe).

How common is CDC45 p.Phe351Cys (c.1052T>G) in the general population?

CDC45 p.Phe351Cys (c.1052T>G) is very rare (popmax 0.000257%, nfe) (gnomAD).

What do computational predictors say about CDC45 p.Phe351Cys (c.1052T>G)?

AlphaMissense predicts likely pathogenic (score 0.6516) — an in-silico prediction, not a clinical call.

CDC45 p.Phe351Cys

c.1052T>G · rs780209184 · VCV1361085

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6516 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000257%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6516	likely pathogenic
REVEL	0.44	indeterminate
SaProt	LLR -9.73	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.99	donor gain · deltas
Pangolin	Δ0.83	gain · loss 0.71 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.0069 · regional, not allelic
Overall
CADD	35.0	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 0.000257% European (non-Finnish) · 3/1,168,496 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000188% 3/1,593,522 alleles · very rare exomes 3/1,441,220 · genomes 0/152,302 · joint denominator

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.Phe351Cys
Coding: c.1052T>G
MANE Select: NM_003504
dbSNP: rs780209184
Type: single nucleotide variant
Location: chr22:19507861 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.59 · 7 PDB

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-phe351cys (accessed [today's date]).

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