Differential splicing plays a key role in creating protein diversity. Differential splicing can be observed between tissues and contribute to their function. We have recently revealed a basic framework that defines the rules that govern splice site choice across eukaryoes (Dent et al, Nature Comm, 2025). However, the exact signals that make a splice site active in one tissue but silent in another remain largely unknown. In this study, we use large-scale computational genomics to figure out what drives tissue-specific splicing in humans. By analysing splice-site usage from GTEx RNA-seq data (20 tissues, over 300 genotyped donors), we identified splicing events that are specific to certain tissues. Looking at the sequences around these sites, we found recurring sequence patterns (motifs) associated with tissue-specific splicing. At the same time, we ran over a million genome-wide association studies (GWAS) to find genetic variants that change splice-site strength in certain tissues, but not others. We created a detailed atlas of splice regulatory variants whose functional impacts differ between tissues. Comparing results across tissues helps us pinpoint variants that act differently depending on the tissue, shedding light on the DNA elements that give splicing its tissue-specific behaviour. Several of these genetic variants have been previously reported be among the variants associated with human disease, including cancer. Our analysis suggests that altered splice-site activity may represent a key mechanistic link, raising the possibility that a subset of these diseases may, in fact, reflect tissue-specific splicing defects. Together, this approach expands our knowledge of splicing regulators and provides a foundation for developing therapies to fix splicing-related defects.