NM_000368.5:c.2194C>T (p.His732Tyr) is a missense variant in TSC1, a gene in which loss-of-function variants cause tuberous sclerosis complex (autosomal dominant). The variant is present in gnomAD v2.1 at an allele frequency of 0.387% (1093/282512 alleles) with 7 homozygotes, and in gnomAD v4.1 at 0.360% (5806/1612416 alleles) with 28 homozygotes. This frequency exceeds the 0.3% threshold for BS1 (strong benign).¹ The presence of 28 homozygous individuals in gnomAD v4.1 is incompatible with a highly penetrant autosomal dominant tumor suppressor disorder; homozygous loss of TSC1 function would be expected to cause severe disease.² Multiple in silico predictors support a benign interpretation: REVEL score 0.338 (below 0.5 pathogenic threshold), BayesDel score -0.064 (negative score), and SpliceAI max delta 0.09 (below 0.2 splicing threshold), meeting BP4 (supporting benign).³ In ClinVar, 23 clinical laboratories classify this variant as Benign and 4 as Likely benign (Variation ID: 5103), meeting BP6 (supporting benign).⁴ PMID:19918125 (Lugnier et al. 2009) characterized hamartin H732Y in vitro and demonstrated reduced tuberin binding (2.3-fold, p<0.05) and aberrant nuclear localization. However, the paper explicitly reported the allele at 0.5% frequency in the normal population and concluded it 'cannot be sufficient to cause TSC or FCD,' describing it as a low-penetrance predisposing variant at most.⁵ Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): one strong benign criterion (BS1) plus two supporting benign criteria (BP4, BP6) yields a final classification of Likely Benign.⁶