NM_014727.2:c.5989C>G (p.Leu1997Val) in KMT2B is extremely rare in population databases, observed in only 1 of 1,613,902 alleles (AF=0.00006%) in gnomAD v4.1 and absent from gnomAD v2.1 and gnomAD-Canada, meeting PM2 at supporting strength.¹ This variant is a missense substitution and does not qualify for PVS1; no pathogenic variants have been reported at the same residue (PS1 not met); no functional studies exist (PS3 not assessed); and no de novo or segregation data are available. Multiple in silico prediction tools do not support a deleterious effect: REVEL score is 0.37 (intermediate), BayesDel score is -0.166 (benign range), and SpliceAI predicts no splicing impact (max delta=0.00). However, this evidence is mixed and does not confidently meet PP3 or BP4.² The only criterion met is PM2 (supporting). Per ACMG/AMP 2015 classification rules (PMID:25741868), a single supporting pathogenic criterion without any benign criteria is insufficient for a likely pathogenic or benign classification.³ Overall classification: Variant of Uncertain Significance (VUS). Additional evidence including functional studies, segregation analysis, case-control data, or clinical correlation is required to resolve the significance of this variant.