The chapter discusses the global impact of unproductive splicing on human gene expression. Alternative splicing (AS) can generate multiple mRNA isoforms from a single gene, but most of these isoforms are lowly expressed and lack cross-species conservation. Mis-splicing, often involving the activation of unconserved 'cryptic' splice sites, introduces frameshifts and premature termination codons (PTCs), leading to rapid degradation by nonsense-mediated decay (NMD). Unproductive transcripts can also result from regulated AS, where splicing factors control their own pre-mRNA splicing, relying on the coupling between AS and NMD. However, the extent to which these isoforms influence gene expression levels and phenotypes is unclear due to the rapid decay of unproductive transcripts. The study uses high-throughput measurements, including nascent RNA-seq (naRNA-seq) and CUT&Tag data, to assess the impact of AS on steady-state gene expression levels. It finds that unproductive splicing is pervasive, with ~2.3% of splicing events targeting transcripts for NMD. The fraction of unproductive splicing correlates with degradation rates, and it is estimated to explain at least 9% of post-transcriptional gene expression variance. Highly expressed and evolutionarily constrained genes have lower rates of unproductive splicing, suggesting that unproductive splicing is generally molecular noise rather than a regulatory mechanism. The study also explores the genetic effects on RNA splicing and expression, using quantitative trait loci (QTL) mapping. It finds that genetic variants that alter expression post-transcriptionally are enriched in splice-altering variants predicted to induce NMD. These variants are particularly enriched in eQTL signal for the host gene and explain a significant portion of the genetic regulation of expression levels. The chapter concludes that AS–NMD plays a major role in the genetic regulation of complex traits and that unproductive splicing is a significant source of molecular noise in gene expression.The chapter discusses the global impact of unproductive splicing on human gene expression. Alternative splicing (AS) can generate multiple mRNA isoforms from a single gene, but most of these isoforms are lowly expressed and lack cross-species conservation. Mis-splicing, often involving the activation of unconserved 'cryptic' splice sites, introduces frameshifts and premature termination codons (PTCs), leading to rapid degradation by nonsense-mediated decay (NMD). Unproductive transcripts can also result from regulated AS, where splicing factors control their own pre-mRNA splicing, relying on the coupling between AS and NMD. However, the extent to which these isoforms influence gene expression levels and phenotypes is unclear due to the rapid decay of unproductive transcripts. The study uses high-throughput measurements, including nascent RNA-seq (naRNA-seq) and CUT&Tag data, to assess the impact of AS on steady-state gene expression levels. It finds that unproductive splicing is pervasive, with ~2.3% of splicing events targeting transcripts for NMD. The fraction of unproductive splicing correlates with degradation rates, and it is estimated to explain at least 9% of post-transcriptional gene expression variance. Highly expressed and evolutionarily constrained genes have lower rates of unproductive splicing, suggesting that unproductive splicing is generally molecular noise rather than a regulatory mechanism. The study also explores the genetic effects on RNA splicing and expression, using quantitative trait loci (QTL) mapping. It finds that genetic variants that alter expression post-transcriptionally are enriched in splice-altering variants predicted to induce NMD. These variants are particularly enriched in eQTL signal for the host gene and explain a significant portion of the genetic regulation of expression levels. The chapter concludes that AS–NMD plays a major role in the genetic regulation of complex traits and that unproductive splicing is a significant source of molecular noise in gene expression.