Is CDC25A p.Ala145Asp (c.434C>A) pathogenic?

CDC25A p.Ala145Asp (c.434C>A) is classified Uncertain significance in CDC25A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-29). AlphaMissense: likely benign (0.1769); Ultra-rare (popmax 0.0222%, nfe).

How common is CDC25A p.Ala145Asp (c.434C>A) in the general population?

CDC25A p.Ala145Asp (c.434C>A) is ultra-rare (popmax 0.0222%, nfe) (gnomAD).

What do computational predictors say about CDC25A p.Ala145Asp (c.434C>A)?

AlphaMissense predicts likely benign (score 0.1769) — an in-silico prediction, not a clinical call.

CDC25A p.Ala145Asp

c.434C>A · VCV3264945

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1769 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0222%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1769	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -5.33	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 4.2	GERP 0.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 22 kb · p 0.0072 · 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 0.0222% European (non-Finnish) · 262/1,179,940 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0191%

Overall 0.0167% 269/1,613,718 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0222%	4,504
Remaining individualsnot grpmax-eligible	0.0064%	15,621
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
African / African-American	0.00267%	37,438

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: CDC25A
Protein: p.Ala145Asp
Coding: c.434C>A
MANE Select: NM_001789
Type: single nucleotide variant
Location: chr3:48180836 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 2 PDB

Full CDC25A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDC25A p.Ala145Gly Uncertain significance ★ ⚠ same residue
CDC25A p.Gln24His Benign ★★ same type
CDC25A p.Ala22Val Uncertain significance ★ ⚠ same type
CDC25A p.Arg10His Uncertain significance ★ ⚠ same type
CDC25A p.Arg157His Uncertain significance ★ ⚠ same type
CDC25A p.Arg175Ser Uncertain significance ★ ⚠ same type
CDC25A p.Arg182Leu Uncertain significance ★ ⚠ same type
CDC25A p.Arg270Gln 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/cdc25a-p-ala145asp (accessed [today's date]).

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