NM_000548.4:c.4751T>C (p.Leu1584Pro) is a missense variant in exon 37 of TSC2. The variant is located within the Rap-GAP domain (residues 1531-1758), a critical functional domain of TSC2 responsible for GTPase-activating protein activity essential for mTORC1 inhibition. Leucine 1584 resides within an alpha-helical segment (1584-1586), and substitution to proline is predicted to disrupt helical structure (PM1_supporting). The variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (PM2_supporting).¹ Multiple in silico tools predict a deleterious effect: REVEL score 0.989 is strongly damaging and BayesDel score 0.569902 supports a deleterious prediction (PP3_supporting).² SpliceAI predicts no splicing impact (max delta score 0.00), indicating the predicted effect is at the protein level rather than through altered splicing.³ No variant-specific functional studies were confirmed. PMID:22903760 tested 78 TSC2 variants for functional effects on TORC1 inhibition, but L1584P could not be verified among those tested from available evidence.⁴ ClinVar reports this variant as Uncertain significance (1 star, single submitter from Labcorp/Invitae), which does not contribute to PP5 or BP6.⁵ No de novo, cosegregation, case-control, or detailed phenotype data are available to support PS2, PS4, PP1, or PP4. With PM1_supporting, PM2_supporting, and PP3_supporting as the only criteria met (3 supporting-level pathogenic criteria), the variant does not reach the threshold for Likely Pathogenic classification under ACMG/AMP 2015 rules. The variant is classified as a Variant of Uncertain Significance (VUS) trending toward pathogenic.⁶