So, host genetic variation in the JAK-STAT signaling axis—particularly in TYK2, IFNAR1/2, and JAK2—profoundly influences COVID-19 susceptibility and severity that lays the groundwork for not only personalized therapeutic strategies, including early immunomodulation tailored to patients with pro-inflammatory JAK variants but also for impaired antiviral signaling. The gene discussed is TYK2; the disease is COVID-19.