Spatial variable genes (SVGs) reveal critical information about tissue architecture, cellular interactions, and disease microenvironments. As spatial transcriptomics (ST) technologies proliferate, accurately identifying SVGs across diverse platforms, tissue types, and disease contexts has become both a major opportunity and a significant computational challenge. Here, we present a comprehensive benchmarking study of 20 state-of-the-art SVG detection methods using human slides from STimage-1K4M, a large-scale resource of ST data comprising 662 slides from more than 18 tissue types. We evaluate each method across a range of biologically and technically meaningful criteria, including recovery of pathologist-annotated domain-specific markers, cross-slide reproducibility, scalability to high-resolution data, and robustness to technical variation. Our results reveal marked differences in performance depending on tissue type, spatial resolution, and study design. Beyond benchmarking, we construct the first cross-tissue atlas of SVGs, enabling comparative analysis of spatial gene programs across cancer and normal tissues. We observe similarities between pairs of tissues that reflect developmental and functional relationships, such as high overlap between thymus and lymph node, and uncover spatial gene programs associated with metastasis, immune infiltration, and tissue-of-origin identity in cancer. Together, our work defines a framework for evaluating and interpreting spatial gene expression and establishes a reference resource for the ST community.

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