Is CDC45 p.Pro89Ser (c.265C>T) pathogenic?

CDC45 p.Pro89Ser (c.265C>T) is classified Conflicting classifications of pathogenicity in CDC45 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-03). AlphaMissense: likely pathogenic (0.6116); Very rare (popmax 0.00204%, nfe).

How common is CDC45 p.Pro89Ser (c.265C>T) in the general population?

CDC45 p.Pro89Ser (c.265C>T) is very rare (popmax 0.00204%, nfe) (gnomAD).

What do computational predictors say about CDC45 p.Pro89Ser (c.265C>T)?

AlphaMissense predicts likely pathogenic (score 0.6116) — an in-silico prediction, not a clinical call.

CDC45 p.Pro89Ser

c.265C>T · rs200116606 · VCV1633514

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6116 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00204%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6116	likely pathogenic
REVEL	0.181	moderately benign-leaning
SaProt	LLR -10.49	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.0069 · regional, not allelic
Overall
CADD	26.2	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 0.00204% European (non-Finnish) · 24/1,178,320 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00875% 141/1,612,174 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.169%	593
Remaining individualsnot grpmax-eligible	0.0128%	7,803
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
European (non-Finnish)grpmax	0.00204%	49,097

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro89Ser
Coding: c.265C>T
MANE Select: NM_003504
dbSNP: rs200116606
Type: single nucleotide variant
Location: chr22:19482750 (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-pro89ser (accessed [today's date]).

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