Herein, we identified residues in the EC1 domain of PCDH1 critical for ANDV and SNV Gn/Gc engagement, including one that influences SNV cellular host range and demonstrated that Gn/Gc:PCDH1 recognition, not just PCDH1 per se, is required for the development of lethal ANDV infection in Syrian hamsters. Here, PCDH1 is linked to infection.