Abstract: Hevin/Sparcl1 (hereafter referred to as Hevin) is an extracellular matrix protein encoded by the SPARCL1 gene. Recently, it has been revealed that Hevin has various functions, such as synapse formation, neuronal migration, inflammation, and angiogenesis (Gongidi et al., 2004; Naschberger et al., 2016; Singh et al., 2016; Liu et al., 2021). In addition, genome-wide association studies uncovered de novo and familial mutations of the SPARCL1 gene associated with a risk for autism spectrum disorder (ASD) (De Rubeis et al., 2014). However, the relationship between ASD-associated Hevin mutant and cellular phenotype has not been clarified. Recently, we have reported that ASD-associated mutation in Hevin reduces secretion efficiency and induces endoplasmic reticulum (ER) stress caused by structural instability (Taketomi et al., 2022). In this perspective, we discuss the relationship between the molecular functions of Hevin and ASD risk (Figure 1A). Also, we introduce our recent findings that link ASD-associated Hevin mutant to the cellular phenotype of ASD.