Is CDC23 p.Pro63Leu (c.188C>T) pathogenic?

CDC23 p.Pro63Leu (c.188C>T) is classified Uncertain significance in CDC23 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-16). AlphaMissense: likely benign (0.228); Ultra-rare (popmax 0.0387%, afr).

How common is CDC23 p.Pro63Leu (c.188C>T) in the general population?

CDC23 p.Pro63Leu (c.188C>T) is ultra-rare (popmax 0.0387%, afr) (gnomAD).

What do computational predictors say about CDC23 p.Pro63Leu (c.188C>T)?

AlphaMissense predicts likely benign (score 0.228) — an in-silico prediction, not a clinical call.

CDC23 p.Pro63Leu

c.188C>T · VCV3998469

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.228 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0387%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.228	likely benign
REVEL	0.265	benign-leaning
SaProt	LLR -11.72	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 6,666 bp · p 0.36 · regional, not allelic
Overall
CADD	21.2	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 0.0387% African / African-American · 29/74,972 alleles

Filtering AF 0.0277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0239%

Overall 0.00223% 36/1,613,884 alleles · ultra-rare exomes 15/1,461,790 · genomes 21/152,094 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0387%	2,585
East Asian	0.00669%	14,957
European (non-Finnish)	0.000339%	294,983

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.Pro63Leu
Coding: c.188C>T
MANE Select: NM_004661
Type: single nucleotide variant
Location: chr5:138213037 (GRCh38)
Gene constraint: LOEUF 0.452 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.74 · 20 PDB
Residue 63: an α-helix

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

Similar variants

CDC23 p.Pro63Ser Uncertain significance ★ ⚠ same residue
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

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-pro63leu (accessed [today's date]).

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