NM_001259.8:c.763C>T (p.His255Tyr) is a missense variant in CDK6, a gene without an established ClinGen CSPEC/VCEP framework. Assessment follows generic ACMG/AMP 2015 guidelines (PMID:25741868).¹ This variant is extremely rare in population databases, present at an allele frequency of 6.2 × 10⁻⁷ (1/1,614,060 alleles, 0 homozygotes) in gnomAD v4.1 and absent from gnomAD v2.1 and gnomAD-Canada, meeting PM2 at supporting level (PM2_Supporting).² Multiple in silico tools predict a benign effect: REVEL score 0.062, BayesDel score -0.465931, and SpliceAI max delta 0.00, meeting BP4 at supporting level (BP4_Supporting).³ No pathogenic criteria above supporting level are met. PVS1 is not applicable (missense variant). PS1-PS5 are not met due to absence from ClinVar and lack of functional, segregation, or de novo data. PM1 and PM5 are not met. PP1-PP5 are not met.⁴ No benign criteria above supporting level are met. BA1 and BS1 are not met (allele frequency far below thresholds). BS2-BS4 are not met. BP1, BP2, BP5, and BP6 are not met. BP3 and BP7 are not applicable.⁵ With one supporting pathogenic criterion (PM2_Supporting) and one supporting benign criterion (BP4_Supporting), the evidence is balanced with no criteria above supporting strength on either side. Under ACMG/AMP 2015 combination rules, this results in a classification of Variant of Uncertain Significance (VUS).⁶