Is CDC25A p.Glu392Lys (c.1174G>A) pathogenic?

CDC25A p.Glu392Lys (c.1174G>A) is classified Uncertain significance in CDC25A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-03). AlphaMissense: ambiguous (0.4625); Very rare (popmax 0.00834%, amr).

How common is CDC25A p.Glu392Lys (c.1174G>A) in the general population?

CDC25A p.Glu392Lys (c.1174G>A) is very rare (popmax 0.00834%, amr) (gnomAD).

What do computational predictors say about CDC25A p.Glu392Lys (c.1174G>A)?

AlphaMissense predicts ambiguous (score 0.4625) — an in-silico prediction, not a clinical call.

CDC25A p.Glu392Lys

c.1174G>A · rs773575919 · VCV2370976

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4625 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4625	ambiguous
REVEL	0.246	benign-leaning
SaProt	LLR -10.10	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP -0.61, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 6,921 bp · p 3.3e-17 · regional, not allelic
Overall
CADD	33.0	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 0.00834% Admixed American · 5/59,988 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00112% 18/1,612,722 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,699
Admixed Americangrpmax	0.00834%	11,998
Remaining individualsnot grpmax-eligible	0.00641%	15,609
European (non-Finnish)	8.48e-05%	1,178,837

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu392Lys
Coding: c.1174G>A
MANE Select: NM_001789
dbSNP: rs773575919
Type: single nucleotide variant
Location: chr3:48165653 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 2 PDB
Residue 392: the rhodanese domain; an α-helix

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

Similar variants

CDC25A p.Gln24His Benign ★★ same type
CDC25A p.Ala145Asp Uncertain significance ★ ⚠ same type
CDC25A p.Ala145Gly Uncertain significance ★ ⚠ 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

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-glu392lys (accessed [today's date]).

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