NM_000435.2:c.3452G>A (p.Gly1151Glu) is a missense variant in NOTCH3, a gene in which missense variants are a well-established cause of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy).¹ This variant is ultra-rare in population databases, absent from gnomAD v2.1 and present in gnomAD v4.1 at an allele frequency of 1.24e-6 (2/1,614,098 alleles, 0 homozygotes), well below the 0.1% PM2 threshold (PM2_Supporting).² In silico analysis with REVEL yields a score of 0.866, predicting a damaging effect on the protein. BayesDel is borderline at 0.474, and SpliceAI predicts no splice impact (max delta 0.02) (PP3_Supporting).³ No variant-specific functional data, de novo observations, case-control studies, segregation data, or ClinVar classifications are available for this variant. The variant is absent from ClinVar and has not been reported in COSMIC or literature.⁴ With only two supporting-level pathogenic criteria (PM2_Supporting, PP3_Supporting) and no benign criteria met, the evidence is insufficient to classify this variant as pathogenic, likely pathogenic, benign, or likely benign under the ACMG/AMP 2015 framework. This variant is classified as a Variant of Uncertain Significance (VUS).⁵