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Objective: Developmental and epileptic encephalopathies (DEEs) can result from dominant, gain of function variants of neuronal ion channels. More than 450 de novo missense variants of the sodium channel gene SCN8A have been identified in individuals with DEE. Methods: We studied a mouse model carrying the patient Scn8a variant p.Asn1768Asp. An AAV‐PHP.eB virus carrying an allele‐specific single guide RNA (sgRNA) was administered by intracerebroventricular injection. Cas9 was provided by an inherited transgene. Results: Allele‐specific disruption of the reading frame of the pathogenic transcript generated out‐of‐frame indels in 1/4 to 1/3 of transcripts throughout the brain. This editing efficiency was sufficient to rescue lethality and seizures. Neuronal hyperexcitability was reduced in cells expressing the virus. Interpretation: The data demonstrate efficient allele‐specific editing of a dominant missense variant and support the feasibility of allele‐specific therapy for DEE epilepsy. ANN NEUROL 2024;96:958–969 [ABSTRACT FROM AUTHOR]