NM_024408.3:c.3570G>C (p.Glu1190Asp) in NOTCH2 is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, supporting a rare variant interpretation.¹ Multiple in silico predictors suggest no significant impact: BayesDel predicts a benign score (-0.045) and SpliceAI indicates no splicing impact (max delta 0.07).² The variant is a novel missense change at a residue not in a known functional domain or mutational hotspot. No functional studies, segregation data, or de novo reports are available.³ Applying generic ACMG/AMP 2015 combination rules: PM2 (supporting pathogenic) and BP4 (supporting benign) are both met. The single supporting pathogenic and single supporting benign criterion do not reach the threshold for Likely Pathogenic or Likely Benign.⁴ This variant is classified as a Variant of Uncertain Significance (VUS).⁵