The variant c.1873C>A (p.Arg625Ser) in SF3B1 alters a residue in a statistically significant mutational hotspot, meeting PM1 at moderate strength. The variant is extremely rare in population databases, present at an allele frequency of 6.2e-07 (1/1,613,940 alleles) in gnomAD v4.1 and absent from gnomAD v2.1, meeting PM2 at moderate strength.¹ Computational evidence is discordant: REVEL predicts a deleterious effect (0.806) but BayesDel predicts a benign effect (0.235), and SpliceAI predicts no splicing impact (delta 0.12). PP3 and BP4 are not met.² No variant-specific publications, ClinVar classifications, de novo reports, functional studies, or segregation data are available. Multiple criteria (PS2, PS3, PS4, PM6, PP1, PP4, BS2, BS3, BS4, BP2, BP5) could not be assessed.³ The variant is absent from ClinVar and has not been classified by any germline reputable source; PP5 and BP6 are not met.⁴ Two moderate pathogenic criteria (PM1, PM2) are met with zero benign criteria met. This falls short of the Likely Pathogenic threshold (≥3 moderate, or ≥2 moderate + ≥2 supporting, or ≥1 strong + ≥1 moderate) per ACMG/AMP 2015 combination rules. The variant is classified as a Variant of Uncertain Significance (VUS).⁵