Background:In 2022, the WHO classified a new subtype of myelodysplastic neoplasms (MDS) with low blast count and SF3B1mutation called MDS- SF3B1. SF3B1 is the major subunit of the SF3B spliceosome complex and is responsible for recognizing 3' splice sites in pre-mRNA for processing into mature mRNA. Mutations in SF3B1have also been observed in other myeloid neoplasms. While MDS- SF3B1has been associated with a better survival outcome, allelic variants such as SF3B1 K666Nare associated with higher-risk MDS, transformation to AML and decreased OS. Additionally, SF3B1 E592Kis more likely to be co-mutated with RUNX1, with a worse prognosis. Thus, not all SF3B1 allelic variants should be treated the same. The IPSS-M model incorporates SF3B1 mutations with different weights depending on co-mutations (i.e. isolated del(5q) or BCOR, BCORL1, RUNX1, NRAS, STAG2, SRSF2 mutations) but did not find a difference based on SF3B1 hotspot mutation. However, these and other studies have focused on specific amino acid substitutions but have not taken into consideration the protein domain structure of SF3B1. Using a large cohort of SF3B1-mutant myeloid malignancies, we determined whether HEAT repeat domain location was associated with differences between SF3B1-mutant myeloid neoplasms when comparing co-mutations and clinical characteristics.