Is CDC23 p.Ser121Tyr (c.362C>A) pathogenic?

CDC23 p.Ser121Tyr (c.362C>A) is classified Uncertain significance in CDC23 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.9965); Very rare (popmax 8.47e-05%, nfe).

How common is CDC23 p.Ser121Tyr (c.362C>A) in the general population?

CDC23 p.Ser121Tyr (c.362C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CDC23 p.Ser121Tyr (c.362C>A)?

AlphaMissense predicts likely pathogenic (score 0.9965) — an in-silico prediction, not a clinical call.

CDC23 p.Ser121Tyr

c.362C>A · VCV4223199

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9965 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9965	likely pathogenic · top 8% in CDC23
REVEL	0.608	indeterminate
SaProt	LLR -15.85	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 8,181 bp · p 0.00013 · regional, not allelic
Overall
CADD	32.0	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 8.47e-05% European (non-Finnish) · 1/1,179,952 alleles

Overall 6.84e-05% 1/1,461,812 alleles · very rare

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.Ser121Tyr
Coding: c.362C>A
MANE Select: NM_004661
Type: single nucleotide variant
Location: chr5:138206557 (GRCh38)
Gene constraint: LOEUF 0.452 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.74 · 20 PDB
Residue 121: an α-helix

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

Similar variants

CDC23 c.1166+2T>G Uncertain significance ★ same type
CDC23 p.Ala68Asp Uncertain significance ★ ⚠ same type
CDC23 p.Arg424Gln Uncertain significance ★ ⚠ same type
CDC23 p.Arg424Trp 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

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-ser121tyr (accessed [today's date]).

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