Is CDC25B p.Arg220Cys (c.658C>T) pathogenic?

CDC25B p.Arg220Cys (c.658C>T) is classified Uncertain significance in CDC25B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely benign (0.1157); Very rare (popmax 0.00439%, sas).

How common is CDC25B p.Arg220Cys (c.658C>T) in the general population?

CDC25B p.Arg220Cys (c.658C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about CDC25B p.Arg220Cys (c.658C>T)?

AlphaMissense predicts likely benign (score 0.1157) — an in-silico prediction, not a clinical call.

CDC25B p.Arg220Cys

c.658C>T · VCV4223206

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1157 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1157	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -7.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.5, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 4,737 bp · p 0.23 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00439% South Asian · 4/91,084 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.0031% 50/1,613,898 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,771
African / African-American	0.004%	24,975
European (non-Finnish)	0.00339%	29,498
Admixed American	0.00333%	29,999
Remaining individualsnot grpmax-eligible	0.0016%	62,470

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: CDC25B
Protein: p.Arg220Cys
Coding: c.658C>T
MANE Select: NM_021873
Type: single nucleotide variant
Location: chr20:3801046 (GRCh38)
Gene constraint: LOEUF 0.641 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.43 · 19 PDB

Full CDC25B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDC25B p.Ala124Val Uncertain significance ★ ⚠ same type
CDC25B p.Ala171Val Uncertain significance ★ ⚠ same type
CDC25B p.Ala231Thr Uncertain significance ★ ⚠ same type
CDC25B p.Ala23Ser Uncertain significance ★ ⚠ same type
CDC25B p.Ala252Asp Uncertain significance ★ ⚠ same type
CDC25B p.Ala463Thr Uncertain significance ★ ⚠ same type
CDC25B p.Ala46Ser Uncertain significance ★ ⚠ same type
CDC25B p.Ala48Ser 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/cdc25b-p-arg220cys (accessed [today's date]).

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