NM_000435.2:c.4688C>T (p.Pro1563Leu) is a missense variant in NOTCH3. It is absent from gnomAD v2.1 (0/242,354 alleles) and ultra-rare in gnomAD v4.1 (1/1,602,340 alleles; AF=6.24e-7), meeting PM2_Supporting.¹ Multiple computational predictors indicate a benign impact: REVEL score 0.08, BayesDel score -0.37, and SpliceAI max delta 0.00. This meets BP4 (supporting benign).² The variant is a missense substitution (not a null variant), so PVS1 is not applicable. It alters a non-cysteine residue (Pro1563) in EGF-like repeat 30, where the majority of established pathogenic NOTCH3 variants affect conserved cysteine residues; PM1 is not met.³ The variant is absent from ClinVar and has no reported functional studies, de novo observations, case-control data, or family segregation data. OncoKB classifies it as 'Unknown Oncogenic Effect.'⁴ In the generic ACMG/AMP 2015 framework, the current evidence yields PM2_Supporting and BP4_Supporting_Benign. These criteria are insufficient for a definitive classification; the variant remains a Variant of Uncertain Significance (VUS) pending additional clinical and functional data.⁵