Is CDC25C p.Pro421Thr (c.1261C>A) pathogenic?

CDC25C p.Pro421Thr (c.1261C>A) is classified Uncertain significance in CDC25C (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-03). AlphaMissense: likely benign (0.126); Rare (popmax 0.165%, mid).

How common is CDC25C p.Pro421Thr (c.1261C>A) in the general population?

CDC25C p.Pro421Thr (c.1261C>A) is rare (popmax 0.165%, mid) (gnomAD).

What do computational predictors say about CDC25C p.Pro421Thr (c.1261C>A)?

AlphaMissense predicts likely benign (score 0.126) — an in-silico prediction, not a clinical call.

CDC25C p.Pro421Thr

c.1261C>A · rs369731708 · VCV2350001

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.126 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.126	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -9.45	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 7.2	GERP -0.094, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 45 kb · p 0.018 · regional, not allelic
Overall
CADD	22.7	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 0.165% Middle Eastern · 10/6,056 alleles

Filtering AF 0.0896% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0681%

Overall 0.015% 242/1,612,576 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.165%	606
South Asian	0.0868%	1,152
Remaining individualsnot grpmax-eligible	0.032%	3,122
Admixed American	0.015%	6,667
European (non-Finnish)	0.0103%	9,741
African / African-American	0.004%	24,993

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: CDC25C
Protein: p.Pro421Thr
Coding: c.1261C>A
MANE Select: NM_001790
dbSNP: rs369731708
Type: single nucleotide variant
Location: chr5:138286033 (GRCh38)
Gene constraint: LOEUF 1.175 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.78 · 6 PDB
Residue 421: the rhodanese domain; a turn

Full CDC25C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDC25C p.Arg136Cys Uncertain significance ★ ⚠ same type
CDC25C p.Arg208Lys Uncertain significance ★ ⚠ same type
CDC25C p.Arg213Cys Uncertain significance ★ ⚠ same type
CDC25C p.Arg26Met Uncertain significance ★ ⚠ same type
CDC25C p.Arg331Cys Uncertain significance ★ ⚠ same type
CDC25C p.Arg370Gly Uncertain significance ★ ⚠ same type
CDC25C p.Arg383Gly Uncertain significance ★ ⚠ same type
CDC25C p.Arg392His 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/cdc25c-p-pro421thr (accessed [today's date]).

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