Is CDC25C p.Ser75Trp (c.224C>G) pathogenic?

CDC25C p.Ser75Trp (c.224C>G) is classified Uncertain significance in CDC25C (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-16). AlphaMissense: ambiguous (0.3485); Ultra-rare (popmax 0.0125%, nfe).

How common is CDC25C p.Ser75Trp (c.224C>G) in the general population?

CDC25C p.Ser75Trp (c.224C>G) is ultra-rare (popmax 0.0125%, nfe) (gnomAD).

What do computational predictors say about CDC25C p.Ser75Trp (c.224C>G)?

AlphaMissense predicts ambiguous (score 0.3485) — an in-silico prediction, not a clinical call.

CDC25C p.Ser75Trp

c.224C>G · rs202006787 · VCV2213882

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3485 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3485	ambiguous
REVEL	0.125	moderately benign-leaning
SaProt	LLR -10.41	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.4	GERP 0.51, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 45 kb · p 0.018 · regional, not allelic
Overall
CADD	24.3	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 0.0125% European (non-Finnish) · 147/1,179,104 alleles

Filtering AF 0.0108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.01% 162/1,612,600 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0128%	7,804
European (non-Finnish)grpmax	0.0125%	8,021
Admixed American	0.00501%	19,980
Finnishnot grpmax-eligible	0.00313%	31,941
African / African-American	0.00134%	74,802
South Asian	0.0011%	91,058

Remaining individuals 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: CDC25C
Protein: p.Ser75Trp
Coding: c.224C>G
MANE Select: NM_001790
dbSNP: rs202006787
Type: single nucleotide variant
Location: chr5:138329618 (GRCh38)
Gene constraint: LOEUF 1.175 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.78 · 6 PDB

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

Similar variants

CDC25C p.Ser75Leu Uncertain significance ★ ⚠ same residue
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

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-ser75trp (accessed [today's date]).

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