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Abstract Chronic low-dose ionizing radiation induces complex genomic instability encompassing both structural variants and point mutations, yet these alterations are typically analyzed as independent events—limiting detection of mechanistic coupling between rearrangement formation and localized mutagenesis at breakpoint junctions. This gap is particularly consequential given the widespread occupational and environmental exposure contexts—nuclear energy, medical imaging, and environmental contamination— where coupled genomic alterations may contribute to cancer risk through mechanisms invisible to type-agnostic analyses. We developed an integrated analytical framework combining temporal pattern tracking, breakpoint-proximal mutation enrichment analysis, and systematic testing across all structural variant types to resolve these coupled dynamics across dose and time. Applying this framework to whole-genome sequencing data from primary human endothelial cells (HUVEC) exposed to chronic low-dose gamma radiation (0.001–2 mGy/hr) over three weeks, we discovered 7.13-fold enrichment of doublet base substitutions (DBS) within 10bp of inversion breakpoints—a signal absent from other structural variant types. This enrichment decayed sharply with distance (to ∼ 1.9 × at 100bp), indicating localized mutagenesis at these junctions. Temporal analysis revealed divergent fates: inversions appeared transiently (100% single-timepoint) while DBS showed greater persistence (9.0% multi-timepoint). Among the INV-DBS events identified, affected genes include 16 high-constraint loci (pLI ≥ 0.9) involved in DNA damage response, signal transduction, and chromatin regulation—pathways critical for maintaining genomic stability. Our framework provides a generalizable approach for investigating structural variant-mutation relationships, with applications to radiation biology, cancer genomics, and mechanistic studies of DNA repair fidelity.