ABSTRACT Cell‐free DNA (cfDNA) in plasma consists of short DNA fragments resulting from a non‐random fragmentation process, with distinct fragmentomic characteristics that are related with their cellular origins. Here, we report that somatic variant signatures in cfDNA markedly differ between non‐cancerous controls and cancer patients, indicating that tumor‐associated signals are retained in these variants. Surprisingly, even in controls, cfDNA molecules harboring somatic variants exhibit cancer‐like fragmentomic characteristics, such as reduced size, decreased DNA methylation, and altered end motif usages and distributions in the nucleosome structure. Further investigations suggest that such cancer‐like traits are associated with somatic variants derived from clonal hematopoiesis. Importantly, these somatic variants‐associated fragmentomic aberrations are more pronounced in cancer patients, enabling cancer diagnosis. In a large pan‐cancer cohort, we utilize AI to integrate genomic, fragmentomic, and epigenomic features to develop diagnostic models named FreeSV and FreeSV+. Leveraging somatic variant‐associated features alone, the FreeSV model achieved area under the ROC curves (AUCs) between 0.81–0.92 across cancer types; however, when genomewide features are also included, the AUCs of FreeSV+ model substantially increased to 0.93–0.99 across cancer types, highlighting the significance of integrative genomic and fragmentomic analyses in cfDNA for cancer liquid biopsy.