NM_001127511.3:c.1636C>T (p.Arg546Ter) is a nonsense variant in APC, a gene where loss of function is the established mechanism for familial adenomatous polyposis.¹ This variant introduces a premature termination codon at position 546, upstream of the last exon-exon junction, predicting nonsense-mediated decay and complete loss of the C-terminal 2297 amino acids including all β-catenin binding and regulatory domains.² The variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (1/1,613,730 alleles; AF=6.2×10⁻⁷), meeting PM2_Supporting under APC VCEP v2.1.0.³ ClinVar classifies this variant as Pathogenic based on submissions from multiple clinical laboratories, though individual case-level phenotype annotation is not publicly available for PS4 assessment.⁴ SpliceAI predicts no cryptic splice impact (max delta=0.01), consistent with this being a straightforward null variant rather than a splicing defect.⁵