NM_005359.5:c.1067C>T (p.Pro356Leu) is a missense variant in exon 9 of SMAD4. It is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting rarity in the general population.¹ Residue Pro356 is located in the SMAD4 MH2 domain (aa 324-552), a well-established critical functional domain that mediates SMAD oligomerization and transcriptional activation. This residue additionally lies within a statistically significant mutational hotspot.² Multiple in silico predictors support a deleterious effect: REVEL score 0.968 (damaging), BayesDel score 0.541 (damaging). SpliceAI predicts no significant splice impact (max delta 0.03).³ This variant has been reported in ClinVar as Uncertain Significance by a single clinical laboratory (Ambry Genetics; ClinVar ID 1782219). It has been observed in 40 somatic cancer samples (COSMIC COSV61685209) and is classified as Likely Oncogenic by OncoKB.⁴ PVS1 is not applicable (missense variant). In silico evidence meets PP3 (supporting). Population absence meets PM2 (moderate). MH2 domain location and hotspot status meet PM1 (moderate). Verified criteria: PM1 (moderate) + PM2 (moderate) + PP3 (supporting). Under ACMG/AMP 2015 combination rules, 2 moderate + 1 supporting is insufficient for Likely Pathogenic (requires ≥3 moderate, or 2 moderate + ≥2 supporting). No benign criteria are met. PS3 (functional) and PP1 (segregation) were not assessed because variant-specific evidence could not be verified in accessible full-text publications. Overall classification: Uncertain Significance (VUS).⁵ Gaps: Variant-specific germline functional studies (PS3) and co-segregation data (PP1) were referenced in exploratory literature review (PMID:20101697, PMID:15031030) but could not be verified — abstracts do not mention this variant and full texts are unavailable. Resolution of these gaps could upgrade the classification to Likely Pathogenic.