NM_003925.3:c.682G>C (p.Val228Leu) is a missense variant in MBD4 exon 3, observed at extremely low frequency in population databases (gnomAD v2.1 AF = 0.011%, 31/282,140 alleles; gnomAD v4.1 AF = 0.0079%, 127/1,614,038 alleles; no homozygotes).¹ Multiple in silico tools unanimously predict a benign effect: REVEL score 0.199, BayesDel score −0.381, SpliceAI max delta 0.00, and CADD 7.985. Repo et al. (2020) also reported in silico predictions as polymorphism, benign, tolerated, and no splicing impact.² This variant has been reported in ClinVar as Likely benign by Ambry Genetics (SCV005618014) and as Uncertain significance by Invitae (SCV003476936). No expert panel review has been performed (ClinVar Variation ID: 2163156).³ The variant was identified in 1 of 440 Finnish patients with uveal melanoma (Repo et al. 2020). The authors considered it likely benign based on in silico predictions and noted no enrichment in cases compared to the Finnish population frequency (0.032%).⁴ No functional studies, segregation data, de novo observations, or case-control association data are available for this variant. MBD4 is not an established gene where missense variants are a common disease mechanism; the primary pathogenic mechanism is loss of function via truncating variants.⁵ Based on generic ACMG/AMP 2015 criteria, the evidence profile consists of PM2_supporting (low population frequency) and BP4_supporting (multiple benign in silico predictions). These opposing criteria result in an overall classification of Uncertain significance.⁶