NM_003925.3:c.89C>T (p.Pro30Leu) is a missense variant in MBD4, a gene in which germline loss-of-function variants cause a multi-tumor predisposition syndrome.¹ This variant is extremely rare in population databases: absent from gnomAD v2.1 and gnomAD-Canada, and observed at an allele frequency of 6.28e-07 (1/1,593,284 alleles) in gnomAD v4.1, meeting PM2 at supporting strength.² MBD4 germline disease is driven by loss-of-function via truncating variants; missense variants in this gene context meet BP1 at supporting benign strength. Multiple orthogonal in silico predictors concordantly predict a benign effect: REVEL score 0.016, BayesDel score -0.660, and SpliceAI max delta 0.00, meeting BP4 at supporting benign strength.³ Applying generic ACMG/AMP 2015 final classification rules (PMID:25741868): two supporting benign criteria (BP1, BP4) are met versus one supporting pathogenic criterion (PM2). The weight of evidence favors a likely benign classification.⁴