Is CDC25B p.Met59Val (c.175A>G) pathogenic?

CDC25B p.Met59Val (c.175A>G) is classified Uncertain significance in CDC25B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely benign (0.22); Ultra-rare (popmax 0.0139%, afr).

How common is CDC25B p.Met59Val (c.175A>G) in the general population?

CDC25B p.Met59Val (c.175A>G) is ultra-rare (popmax 0.0139%, afr) (gnomAD).

What do computational predictors say about CDC25B p.Met59Val (c.175A>G)?

AlphaMissense predicts likely benign (score 0.22) — an in-silico prediction, not a clinical call.

CDC25B p.Met59Val

c.175A>G · VCV4650817

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.22 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0139%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.22	likely benign
REVEL	0.407	indeterminate
SaProt	LLR -5.97	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9	GERP 1.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 4,737 bp · p 0.23 · regional, not allelic
Overall
CADD	24.3	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 0.0139% African / African-American · 10/71,966 alleles

Filtering AF 0.0075% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0057%

Overall 0.000829% 13/1,567,724 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0139%	7,197
East Asian	0.00242%	41,296
European (non-Finnish)	0.000172%	582,849

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.Met59Val
Coding: c.175A>G
MANE Select: NM_021873
Type: single nucleotide variant
Location: chr20:3796706 (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-met59val (accessed [today's date]).

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