We also provide evidence that PVOD disease–causing substitutions L643R and R585Q in the Gcn2 kinase domain impair Gcn2 activation by accumulation of uncharged tRNAs invoked by HF treatment, but that R585Q Gcn2 can be activated by Gcn2iB (Fig. 8, A–D). Here, EIF2AK4 is linked to pulmonary venoocclusive disease.