Is CDS1 p.Pro421Ser (c.1261C>T) pathogenic?

CDS1 p.Pro421Ser (c.1261C>T) is classified Uncertain significance in CDS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-11). AlphaMissense: ambiguous (0.5583); Very rare (popmax 0.000254%, nfe).

How common is CDS1 p.Pro421Ser (c.1261C>T) in the general population?

CDS1 p.Pro421Ser (c.1261C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CDS1 p.Pro421Ser (c.1261C>T)?

AlphaMissense predicts ambiguous (score 0.5583) — an in-silico prediction, not a clinical call.

CDS1 p.Pro421Ser

c.1261C>T · VCV3489769

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5583 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5583	ambiguous
REVEL	0.228	benign-leaning
SaProt	LLR -10.01	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 7.7	GERP 2.5, phastCons 1
Overall
CADD	23.8	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 0.000254% European (non-Finnish) · 3/1,179,406 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,460,440 alleles · very rare

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: CDS1
Protein: p.Pro421Ser
Coding: c.1261C>T
MANE Select: NM_007194 · reported on NM_001263
Type: single nucleotide variant
Location: chr4:84648561 (GRCh38)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 421: an α-helix; the protein kinase domain

Full CDS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHEK2 p.Leu421His Uncertain significance ★★ ⚠ same residue
CHEK2 p.Leu421Arg Uncertain significance ★ ⚠ same residue
CHEK2 p.Leu421Pro Uncertain significance ★ ⚠ same residue
CHEK2 p.Leu421= Likely benign ★ same residue
CHEK2 c.1008+1G>A Likely pathogenic ★★ same type
CHEK2 c.1008+1G>T Likely pathogenic ★★ same type
CHEK2 c.1008+2T>A Likely pathogenic ★★ same type
CHEK2 c.1008+2T>G Likely pathogenic ★★ 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/cds1-p-pro421ser (accessed [today's date]).

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