Is CDC23 p.Arg424Trp (c.1270C>T) pathogenic?

CDC23 p.Arg424Trp (c.1270C>T) is classified Uncertain significance in CDC23 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely pathogenic (0.5856); Very rare (popmax 0.00167%, amr).

How common is CDC23 p.Arg424Trp (c.1270C>T) in the general population?

CDC23 p.Arg424Trp (c.1270C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CDC23 p.Arg424Trp (c.1270C>T)?

AlphaMissense predicts likely pathogenic (score 0.5856) — an in-silico prediction, not a clinical call.

CDC23 p.Arg424Trp

c.1270C>T · rs746178873 · VCV2483552

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5856 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5856	likely pathogenic
REVEL	0.384	indeterminate
SaProt	LLR -11.39	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.76, phastCons 1
Regional constraint	o/e 0.52	unconstrained · MANE · 9,396 bp · p 8.3e-19 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.00167% Admixed American · 1/60,004 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000547% 8/1,461,866 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,004
European (non-Finnish)	0.000593%	168,574

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: CDC23
Protein: p.Arg424Trp
Coding: c.1270C>T
MANE Select: NM_004661
dbSNP: rs746178873
Type: single nucleotide variant
Location: chr5:138192285 (GRCh38)
Gene constraint: LOEUF 0.452 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.74 · 20 PDB
Residue 424: an α-helix

Full CDC23 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDC23 p.Arg424Gln Uncertain significance ★ ⚠ same residue
CDC23 c.1166+2T>G Uncertain significance ★ same type
CDC23 p.Ala68Asp Uncertain significance ★ ⚠ same type
CDC23 p.Arg585His Uncertain significance ★ ⚠ same type
CDC23 p.Asn110His Uncertain significance ★ ⚠ same type
CDC23 p.Asn23Tyr Uncertain significance ★ ⚠ same type
CDC23 p.Asn287Ser Uncertain significance ★ ⚠ same type
CDC23 p.Asn581Ser 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/cdc23-p-arg424trp (accessed [today's date]).

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