MBD4 NM_001276270.2:c.1382A>G (p.Asn461Ser) is a missense variant in exon 5 encoding a non-conservative amino acid substitution from asparagine to serine at codon 461. This variant is present in gnomAD v4.1 at an allele frequency of 0.202% (3,262/1,614,054 alleles, including 8 homozygotes) and in gnomAD v2.1 at 0.169% (479/282,746 alleles, including 2 homozygotes), indicating it is not a rare variant in the general population.¹ Multiple lines of in silico evidence suggest no significant impact on the gene product: BayesDel scores -0.063 (benign) and SpliceAI predicts no splicing impact (max delta score 0.15). REVEL scores 0.54 (borderline deleterious) but does not overcome the preponderance of benign computational evidence (BP4 supporting).² No variant-specific functional studies, segregation data, de novo observations, or case-control studies were identified in the literature or ClinVar submissions.³ ClinVar classifies this variant as Likely benign based on submissions from multiple clinical laboratories (4 Likely benign, 2 Uncertain significance), though the aggregate review status remains single-submitter level.⁴ Overall, the only criterion met is BP4 at supporting strength. No pathogenic criteria are met. Insufficient evidence exists to classify this variant as either pathogenic or likely pathogenic; the classification is Uncertain Significance (VUS). The population frequency data and clinical laboratory consensus lean toward a benign interpretation but do not meet formal benign classification thresholds.