NM_005359.5:c.1081C>A (p.Arg361Ser) in SMAD4 is absent from all population databases (gnomAD v2.1, v4.1, Canada), meeting PM2 (supporting).¹ The variant lies in the MH2 domain of SMAD4 at codon 361, a well-established mutational hotspot where multiple pathogenic missense changes (p.Arg361Cys, p.Arg361His, p.Arg361Leu) have been independently reported in patients with juvenile polyposis syndrome and JP-HHT syndrome, meeting PM1 (moderate).² p.Arg361Ser is a novel missense change at a residue where different pathogenic missense variants are established: p.Arg361Cys (JPS and HHT), p.Arg361His (de novo JPS), and p.Arg361Leu (JP-HHT), meeting PM5 (moderate).³ Multiple in silico tools predict a deleterious effect: REVEL score 0.912 and BayesDel score 0.534, meeting PP3 (supporting).⁴ SMAD4 is a gene with a well-established role in disease through missense variation, with numerous pathogenic germline missense mutations reported across the MH2 domain and a low rate of benign missense variation, meeting PP2 (supporting).⁵ This variant has been classified as Likely pathogenic by a clinical diagnostic laboratory (Labcorp Genetics/Invitae; SCV002282679) in ClinVar with criteria provided, meeting PP5 at supporting strength.⁶ No benign criteria are met. BA1 and BS1 are not satisfied (variant absent from population databases). BP4 is not met (in silico tools predict damaging). BP1 is not applicable (SMAD4 missense variants are a known disease mechanism). BS3 is not met (no evidence of neutral functional effect). Applying generic ACMG/AMP 2015 combination rules: 2 moderate criteria (PM1 + PM5) with supporting evidence (PM2 + PP2 + PP3 + PP5) meets the threshold for Likely Pathogenic. This classification is consistent with the ClinVar record (Likely pathogenic, single submitter).⁷