Is CDS1 p.Pro336Ala (c.1006C>G) pathogenic?

CDS1 p.Pro336Ala (c.1006C>G) is classified Uncertain significance in CDS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely benign (0.0541); Ultra-rare (popmax 0.0192%, amr).

How common is CDS1 p.Pro336Ala (c.1006C>G) in the general population?

CDS1 p.Pro336Ala (c.1006C>G) is ultra-rare (popmax 0.0192%, amr) (gnomAD).

What do computational predictors say about CDS1 p.Pro336Ala (c.1006C>G)?

AlphaMissense predicts likely benign (score 0.0541) — an in-silico prediction, not a clinical call.

CDS1 p.Pro336Ala

c.1006C>G · rs771670125 · VCV2347977

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0541 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0192%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0541	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -6.37	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 1.7	GERP -2.2, phastCons 0.99
Overall
CADD	7.345	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0192% Admixed American · 11/57,166 alleles

Filtering AF 0.0108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00831%

Overall 0.000688% 11/1,599,926 alleles · ultra-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.Pro336Ala
Coding: c.1006C>G
MANE Select: NM_007194 · reported on NM_001263
dbSNP: rs771670125
Type: single nucleotide variant
Location: chr4:84640964 (GRCh38)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 336: 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.Gln336Ter Pathogenic/Likely pathogenic ★★ same residue
CHEK2 p.Gln336Arg Uncertain significance ★★ ⚠ same residue
CHEK2 p.Gln336His Uncertain significance ★★ ⚠ same residue
CHEK2 p.Gln336Pro Uncertain significance ★★ ⚠ same residue
CHEK2 p.Gln336= Conflicting classifications of pathogenicity ★ same residue
CHEK2 p.Gln336fs Likely pathogenic ★ same residue
CHEK2 c.1008+1G>A Likely pathogenic ★★ same type
CHEK2 c.1008+1G>T 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-pro336ala (accessed [today's date]).

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