Heterozygous missense mutations in COPA, encoding coatomer protein subunit alpha (COPA), cause an interferonopathy mainly associating lung, joint and kidney involvement. This rare autoinflammatory disease is characterised by variable expression and a remarkably high frequency of clinical non-penetrance. Lung features, predominantly chronic diffuse alveolar haemorrhage (DAH), are observed in almost patients and can result in end-stage respiratory insufficiency. The initially described phenotype was broadened to include isolated DAH or lupus nephritis. Rare manifestations reminiscent of other monogenic interferonopathies occur. This indicates the need for careful clinical evaluation in patients with suspicion or diagnosis of COPA syndrome. Considering the dominant inheritance model and the highly variable phenotype, ranging from severe multi-organic disorder to non-penetrance, a careful family screening is recommended. New insights in disease pathogenesis have linked COPA mutations to STING-mediated interferon signalling. Beside a variable efficacy of ‘classical’ immunosuppressive drugs, Janus kinase (JAK) inhibitors constitute a promising treatment in COPA syndrome, and further targeted therapies are awaited.