MYD88 c.818T>C (p.Leu273Pro), corresponding to the canonical L265P mutation, is a well-characterized gain-of-function missense variant in the TIR domain BB-loop (PM1_moderate).¹ Multiple independent functional studies demonstrate that this variant constitutively activates NF-kappaB and JAK/STAT signaling, confers cytokine-independent survival, and that mutant-specific knockdown or pharmacologic inhibition is selectively toxic to MYD88-mutant cells (PS3_strong).² The variant is highly enriched in affected individuals, detected in approximately 90% of Waldenstrom macroglobulinemia cases and recurrent in ABC DLBCL and IgM-MGUS, compared to an extremely low population frequency of 0.0026-0.0052% in gnomAD with zero homozygotes (PS4_strong).³ The variant is absent or extremely rare in population databases, with gnomAD v2.1 AF=5.17e-05 and v4.1 AF=2.60e-05, both well below the 0.1% threshold (PM2_supporting).⁴ In silico predictors support a deleterious effect: REVEL score of 0.735 exceeds the pathogenicity threshold of 0.5, though BayesDel (0.13148) is borderline and SpliceAI predicts no splicing impact (PP3_supporting).⁵ All benign criteria were assessed and none were met. BS3 is specifically contradicted by well-established functional evidence of a gain-of-function damaging effect. BA1 and BS1 are not met as population frequencies remain well below benign thresholds.⁶ Applying generic ACMG/AMP 2015 combination rules: 2 Strong (PS3, PS4) + 1 Moderate (PM1) + 2 Supporting (PM2, PP3) meets the threshold for Pathogenic (>=2 Strong).⁷ CAVEAT: The evidence supporting PS3_strong and PS4_strong derives predominantly from somatic tumor studies. The variant is almost exclusively observed as a somatic mutation in hematologic malignancies. The germline ACMG/AMP framework is being applied to a variant with a somatic disease mechanism. Classification should be interpreted with this context, and human review is recommended to confirm the appropriateness of this germline-classification for the clinical indication.