Tubular aggregate myopathy (TAM) is a progressive skeletal muscle disease associated with gain-of-function mutations in the ER Ca²⁺ sensor STIM1 that mediates store-operated Ca²⁺ entry (SOCE) across the Ca²⁺-release-activated (CRAC) Ca²⁺ channel ORAI1. A frameshift mutation in STIM1 inactivation domain, STIM1^I484R, was identified in a TAM patient and reported to decrease SOCE. Using ion imaging and electrophysiology, we show that the STIM1^I484R mutation instead renders STIM1 constitutively active. STIM1^I484R was less efficient than native STIM1 when expressed alone but enhanced SOCE and increased basal Ca²⁺ and Mn²⁺ influx when expressed together with ORAI1, generating larger pre-activated CRAC currents lacking slow Ca²⁺-dependent inhibition (SCDI). STIM1^I484R was pre-recruited in plasma membrane clusters when co-expressed with ORAI1, as were mutants truncated at the frameshift residue or lacking EB-1-binding, which recapitulated STIM1^I484R gain-of-function. When expressed alone in human primary myoblasts, STIM1^I484R was pre-recruited in large clusters and increased basal Ca²⁺ entry. These observations establish that STIM1^I484R confers a gain of CRAC channel function due to the loss of critical inhibitory C-terminal domains that prevent STIM1 binding to ORAI1, enable STIM1 trapping by microtubules, and mediate SCDI, providing a mechanistic explanation for the muscular defects of TAM patients bearing this mutation.