PHACTR1(phosphatase and actin regulators) plays a key role in cortical migration and synaptic activity by binding and regulating G-actin and PPP1CA. Patients with variants in PHACTR1 can have a phenotype of developmental encephalopathy in addition to infantile epileptic spasms syndrome (IESS). Using AlphaFold-Multimer, our findings indicate that PHACTR1 and G-actin binding sequences overlap with PPP1CA at the RPEL3 domain. In addition, patients carrying missense variants located at the PHACTR1-PPP1CA or PHACTR1-G-actin interfaces consistently exhibit the IESS phenotype. Our study confirmed that the variants affect the binding of PHACTR1 to G-actin or PPP1CA, resulting in neurological disorders in patients. (By Zhao Xu, https://jmg.bmj.com/content/early/2024/01/25/jmg-2023-109638 )