Pre-cursor messenger RNA splicing is an essential process required to maturate most transcripts in the human genome by excising non-coding introns and ligating coding exon sequences, and when mis-regulated can lead to disease. This is carried out by a dynamic ribonucleoprotein complex called the spliceosome. To generate functional products, this RNA-protein enzyme must recognize and activate the correct sequence motifs that define a given intron. However, these splice site sequences are highly variable across the ~200,000 introns encoded in the human genome. SF3B1 is an integral component of the spliceosome and known to play a role in activating the cognate branch point adenosine that later acts in the first chemical reaction of splicing. SF3B1 is also the most frequently mutated splicing factor found to drive many bloodborne cancers like Myelodysplastic syndromes. Remarkably, these mutations occur in dozens of positions across a large region of the protein, over 500 amino acids in length, with a clear hotspot cluster that resides in the same region that is known to bind the spliceosomal helicase Prp5 and directly interacts with splice site sequences of the intron. It is unknown how these variants lead to splicing mis-regulation, or even whether these mutations all lead to a similar molecular defect. In this work, I will describe the massively parallel and high-throughput methods I employed to interrogate this analogous disease hotspot region in the highly conserved ortholog Prp10 from the fission yeast, Schizosaccharomyces pombe. I screened Prp10 mutants for defective splice site selection and then employed a splicing informative sequencing method developed in my lab to interrogate the genome for molecular changes. I learned that these mutations reveal cryptic splice site usage as compared to the wildtype strain and a canonical globally splicing defective strain. I conclude that mutations in the cancer driving region of SF3B1/ Prp10 lower branch point fidelity and modestly disable proofreading.