Our innate immune responses to viral RNA are vital defenses . Long cytosolic double-stranded RNA (dsRNA) is recognized by MDA5 . The ATPase activity of MDA5 contributes to its dsRNA binding selectivity . Mutations that reduce RNA selectivity can cause autoimmune disease . Here, we show how the disease-associated MDA5 variant M854K perturbs MDA5-dsRNA recognition . M854K MDA5 constitutively activates interferon signaling in the absence of exogenous RNA . M854K MDA5 lacks ATPase activity and binds more tightly to synthetic Alu: Alu dsRNA . CryoEM structures MDA5-dsRNA filaments at different stages of ATP hydrolysis show that the K854 side-chain forms polar bonds that constrain the conformation of MDA5 subdomains, disrupting key steps in the ATPase cycle-RNA footprint expansion and helical twist modulation . The M854K mutation inhibits ATP-dependent RNA proofreading via a novel allosteric mechanism, allowing MDA5 to form signaling complexes on endogenous RNAs . This work provides new insights on how MDA5 recognizes dsRNA in health and disease.