Alternative splicing (AS) in human genes is widely viewed as a mechanism for enhancing proteomic diversity. However, AS can also impact gene expression levels without increasing protein diversity by producing 'unproductive' transcripts that are targeted for rapid degradation by nonsense-mediated decay (NMD). This study analyzed population-scale genomic data across eight molecular assays to better understand the impact of AS–NMD relative to other regulatory mechanisms. The results show that unproductive splicing is more prevalent than previously estimated, with 15% of transcript molecules from protein-coding genes being unproductive. These unproductive transcripts are often targeted by NMD, and the study finds that GWAS trait-associated loci explained by AS are as often associated with NMD-induced expression level differences as with differences in protein isoform usage. The findings suggest that much of the impact of AS is mediated by NMD-induced changes in gene expression rather than diversification of the proteome. The study also shows that unproductive splicing is pervasive, with a significant portion of transcripts being targeted by NMD. The results indicate that AS–NMD plays a major role in regulating gene expression levels, and that unproductive splicing events are more common than previously thought. The study also highlights the importance of AS–NMD in complex trait biology, showing that splicing-mediated NMD contributes to complex trait biology. The study concludes that the molecular impact of AS is largely shouldered by NMD, which regulates protein output by targeting unproductive transcripts for degradation. The study also shows that AS–NMD has a significant impact on gene expression levels, and that unproductive splicing events can have variable effects on expression. The study suggests that future research will reveal a preponderance of cases where regulated AS functions by tuning protein expression levels rather than by creating protein diversity. The study also highlights the importance of AS–NMD in understanding the regulatory mechanisms underlying genetic associations for complex traits.Alternative splicing (AS) in human genes is widely viewed as a mechanism for enhancing proteomic diversity. However, AS can also impact gene expression levels without increasing protein diversity by producing 'unproductive' transcripts that are targeted for rapid degradation by nonsense-mediated decay (NMD). This study analyzed population-scale genomic data across eight molecular assays to better understand the impact of AS–NMD relative to other regulatory mechanisms. The results show that unproductive splicing is more prevalent than previously estimated, with 15% of transcript molecules from protein-coding genes being unproductive. These unproductive transcripts are often targeted by NMD, and the study finds that GWAS trait-associated loci explained by AS are as often associated with NMD-induced expression level differences as with differences in protein isoform usage. The findings suggest that much of the impact of AS is mediated by NMD-induced changes in gene expression rather than diversification of the proteome. The study also shows that unproductive splicing is pervasive, with a significant portion of transcripts being targeted by NMD. The results indicate that AS–NMD plays a major role in regulating gene expression levels, and that unproductive splicing events are more common than previously thought. The study also highlights the importance of AS–NMD in complex trait biology, showing that splicing-mediated NMD contributes to complex trait biology. The study concludes that the molecular impact of AS is largely shouldered by NMD, which regulates protein output by targeting unproductive transcripts for degradation. The study also shows that AS–NMD has a significant impact on gene expression levels, and that unproductive splicing events can have variable effects on expression. The study suggests that future research will reveal a preponderance of cases where regulated AS functions by tuning protein expression levels rather than by creating protein diversity. The study also highlights the importance of AS–NMD in understanding the regulatory mechanisms underlying genetic associations for complex traits.