COL4A2 is the encoding gene of the α2 chains of type IV collagen, and missense mutations of COL4A2 is correlated with multiple diseases. However, the association of COL4A2 mutations with epilepsy remains elusive. Here, we aimed to explore the function of COL4A2 mutations in the development of epilepsy. We performed a full spectrum of family-enhanced whole-exome sequencing on a family lineage and examined the genetic change on COL4A2 gene. The kainic acid (KA)-induced in vivo model and lipopolysaccharide (LPS)-induced in vitro model were established. The production and secretion of inflammation cytokines were measured by qPCR, western blotting, and ELISA assay. Neuron damages and astrocyte activation were checked by Nissle and GFAP immunofluorescence staining. One heterozygous variant was detected in the COL4A2 gene: c.1148C>T(p.Pro383Leu). COL4A2 mutation significant induced the exacerbation of seizures and impaired the learning and memory phenotype of the KA rats. COL4A2 mutation promoted the hippocampal astrocyte activation, enhanced hippocampal neuronal injury in the rats. The levels of iNOS, COX-2, IL-1β, IL-6, and TNF-α elevated in KA-treated rats and LPS-treated astrocytes were further induced by COL4A2 mutation. Mechanically, COL4A2 mutation stimulated JAK/STAT signaling. JAK2 and STAT3 phosphorylation was promoted by COL4A2 mutation and JAK/STAT signaling inhibitor WP1066 could blocked the effect in primary astrocytes and CTX-TNA cells. These data indicated that a new identified COL4A2 mutation contributed to astrocyte activation by activating JAK/STAT signaling in epilepsy. Our findings provided a novel mechanism and treatment target of COL4A2 related epilepsy.