Is CDC25C p.Arg136His (c.407G>A) pathogenic?

CDC25C p.Arg136His (c.407G>A) is classified Likely benign in CDC25C (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-12). AlphaMissense: likely benign (0.0629); Ultra-rare (popmax 0.0164%, mid).

How common is CDC25C p.Arg136His (c.407G>A) in the general population?

CDC25C p.Arg136His (c.407G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CDC25C p.Arg136His (c.407G>A)?

AlphaMissense predicts likely benign (score 0.0629) — an in-silico prediction, not a clinical call.

CDC25C p.Arg136His

c.407G>A · rs372372878 · VCV2595053

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0629 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0629	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -6.99	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 -0.93	GERP -0.93
Regional constraint	o/e 0.90	unconstrained · MANE · 45 kb · p 0.018 · regional, not allelic
Overall
CADD	1.41	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0123%

Overall 0.0126% 203/1,613,964 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.015%	6,667
European (non-Finnish)	0.0148%	6,743
Remaining individualsnot grpmax-eligible	0.0128%	7,810
East Asian	0.00668%	14,965
South Asian	0.00659%	15,180
Finnishnot grpmax-eligible	0.00156%	64,024

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.Arg136His
Coding: c.407G>A
MANE Select: NM_001790
dbSNP: rs372372878
Type: single nucleotide variant
Location: chr5:138325867 (GRCh38)
Gene constraint: LOEUF 1.175 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.78 · 6 PDB
Residue 136: the 'disordered' region

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

Similar variants

CDC25C p.Arg136Cys Uncertain significance ★ ⚠ same residue
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-arg136his (accessed [today's date]).

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