Is CDS1 p.Pro351Thr (c.1051C>A) pathogenic?

CDS1 p.Pro351Thr (c.1051C>A) is classified Uncertain significance in CDS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: likely pathogenic (0.8239); Very rare (popmax 0.00333%, amr).

How common is CDS1 p.Pro351Thr (c.1051C>A) in the general population?

CDS1 p.Pro351Thr (c.1051C>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CDS1 p.Pro351Thr (c.1051C>A)?

AlphaMissense predicts likely pathogenic (score 0.8239) — an in-silico prediction, not a clinical call.

CDS1 p.Pro351Thr

c.1051C>A · VCV4651681

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8239 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8239	likely pathogenic
REVEL	0.527	indeterminate
SaProt	LLR -12.34	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.7, phastCons 1
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00333% Admixed American · 2/59,992 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000137% 2/1,456,706 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.Pro351Thr
Coding: c.1051C>A
MANE Select: NM_007194 · reported on NM_001263
Type: single nucleotide variant
Location: chr4:84643042 (GRCh38)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 351: an α-helix; a binding site; the protein kinase domain

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

Similar variants

CHEK2 p.Glu351Ala Uncertain significance ★★ ⚠ same residue
CHEK2 p.Glu351Asp Uncertain significance ★★ ⚠ same residue
CHEK2 p.Glu351Gln Uncertain significance ★★ ⚠ same residue
CHEK2 p.Glu351Gly Uncertain significance ★★ ⚠ same residue
CHEK2 p.Glu351Lys Uncertain significance ★★ ⚠ same residue
CHEK2 p.Glu351fs Pathogenic ★ same residue
CHEK2 p.Glu351_Leu354del Uncertain significance ★ same residue
CHEK2 c.1008+1G>A 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-pro351thr (accessed [today's date]).

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