NM_000548.5:c.5186G>A (p.Arg1729His) in TSC2 is a missense variant in exon 41. PVS1 is not applicable as this is not a null variant.¹ This variant is present at very low frequency in gnomAD v2.1 (AF=0.00607%, 17/280,130 alleles) and gnomAD v4.1 (AF=0.00355%, 57/1,604,608 alleles), with no homozygotes observed, meeting PM2 at supporting strength.² This variant has been classified as Likely benign by three clinical laboratories (GeneDx, Ambry Genetics, Labcorp Genetics) and as Benign by two clinical laboratories in ClinVar (variation ID 207786), meeting BP6 at supporting benign strength.³ In silico predictions are conflicting: REVEL score is 0.811 (damaging) while BayesDel score is 0.179 (benign) and SpliceAI predicts no splice impact (max delta 0.00). Neither PP3 nor BP4 can be applied due to mixed computational evidence.⁴ No variant-specific functional studies, de novo observations, cosegregation data, or case-control evidence were identified for NM_000548.5:c.5186G>A in the reviewed literature. OncoKB reports Unknown Oncogenic Effect.⁵ No pathogenic classification was reported by any ClinVar submitter. PS5 and PP5 are not met.⁶ Allele frequency does not meet BA1 (>1%) or BS1 (>0.3%) thresholds. No homozygotes have been observed, so BS2 is not met.⁷ With PM2 (supporting pathogenic) and BP6 (supporting benign) as the only scorable criteria, these opposing supporting-level criteria effectively neutralize each other. The variant remains a Variant of Uncertain Significance under generic ACMG/AMP 2015 rules.⁸