NM_004304.4:c.4148T>C (p.Ile1383Thr) is a missense variant in exon 28 of the ALK gene. It is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=6.82e-6, 11/1,613,822 alleles, 0 homozygotes).¹ In silico analysis with REVEL predicts a damaging effect (score=0.861), though additional predictors are equivocal (BayesDel score=0.373; SpliceAI max delta=0.0). Ambry Genetics cited in silico evidence (PP3) in their ClinVar submission.² ClinVar Variation ID 575890: classified as Uncertain Significance by 2 clinical laboratories (review status: criteria provided, single submitter). No expert panel classification exists.³ No variant-specific functional data, cosegregation data, case-control data, or de novo reports were identified in the literature. OncoKB classifies this variant as Unknown Oncogenic Effect.⁴ This variant is not a null variant (PVS1 not applicable) and does not fall in a statistically significant mutational hotspot (PM1 not met). No same-residue pathogenic comparators were identified (PM5 not applicable).⁵ No benign criteria are met: the variant is too rare for BA1/BS1, not observed in homozygous state (BS2 not met), and no benign functional evidence exists (BS3 not met). In silico predictors are mixed and do not support multiple lines of benign evidence (BP4 not met). BP1 is not applicable as ALK missense variants are established disease-causing mechanisms.⁶