Vold et al. studied two SNAP-25 variants with different clinical severity. Variants destabilize the SNARE complex and reduce binding to the Munc18-1:VAMP2:syntaxin-1 acceptor complex, with correlated effects on neurotransmitter release. Effects of co-expression of variant and wild-type SNAP-25 were modeled by assuming the co-existence of both species in a ring of SNARE complexes.