In sharp contrast, two autism spectrum disorder-related SHANK3 variants (R12C and L68P) within the SPN domain that are unable to bind to Rap1–GTP (Lilja et al., 2017; Mameza et al., 2013) failed to block activation of Rap1 or αVβ3 in response to optogenetic recruitment of talin to the plasma membrane of endothelial cells (Fig. 3D,E). Here, SHANK3 is linked to autism spectrum disorder.