NM_002944.2:c.6609C>A (p.Asp2203Glu) is a rare missense variant in ROS1, present in gnomAD v4.1 at extremely low frequency (AF=2.50×10⁻⁶, 4/1,600,906 alleles, 0 homozygotes) and absent from gnomAD v2.1 and gnomAD-Canada, meeting PM2 at supporting level.¹ Multiple in silico tools predict a benign effect: REVEL score is 0.14, BayesDel score is −0.455671, and SpliceAI predicts no splice impact (max delta=0.01). Additionally, the substitution is biochemically conservative (Asp→Glu, both acidic residues), meeting BP4 at supporting level.² This variant is absent from ClinVar with no clinical assertions, has not been reported in COSMIC, does not lie in a statistically significant mutational hotspot, and has no variant-specific functional evidence (OncoKB: Unknown Oncogenic Effect). No publications mention this specific variant.³ With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced. No other criteria are met. This variant is classified as a Variant of Uncertain Significance (VUS) under ACMG/AMP 2015 generic framework.⁴