Abstract only Background: Mavacamten is a small molecule inhibitor of cardiac myosin that was developed based on insights into the molecular basis of hypertrophic cardiomyopathy (HCM). In the phase 3 EXPLORER-HCM trial (NCT03470545), patients showed consistent benefit in the primary endpoint with mavacamten treatment vs placebo while subgroup analysis of patients with pathogenic or likely pathogenic variants in a broad panel of HCM-related genes, revealed a slightly more favorable response. However, it is unknown how patients specifically with sarcomere gene variants responded. Aims: To assess the effect of HCM-specific sarcomere gene variants on response to mavacamten. Methods: Sequencing using a 60 gene panel (Invitae) was optional in EXPLORER-HCM. In this exploratory analysis, responses to mavacamten vs placebo for the primary, secondary, and exploratory endpoints were analysed. Patients were grouped based on sarcomere gene variant status (positive for pathogenic/likely pathogenic/variants of uncertain significance SARC+, negative SARC–) or no sequencing). Analyses were adjusted for clinically relevant variables. Results: Of 190/251 patients sequenced, 73 were SARC+ (mavacamten, n = 33; placebo, n = 40), 117 were SARC– (mavacamten, n = 57; placebo, n = 60) and 61 had no panel sequencing (mavacamten, n = 33; placebo, n = 28). Mavacamten treatment showed a favorable response for the primary endpoint vs placebo, for SARC+ (odds ratio OR, 4.43 95% CI, 1.56-12.58), and for SARC– (OR, 2.52 95% CI, 0.99-6.42) ( Figure ). Improvements with mavacamten vs placebo were observed in both SARC+ and SARC– subgroups for change from baseline to week 30 in post-exercise left ventricular outflow tract gradient, and peak oxygen consumption, and in New York Heart Association class. Conclusions: In this exploratory subgroup analysis, mavacamten treatment benefit was observed both in patients with and without sarcomere gene variants.