The findings emerging from our in vitro study suggest that the new genetic variant identified in exon 1 of the α-GLA gene codifying the signal peptide of GLA, c.13 A/G, could promote ER stress and increase the cellular expression of some markers of apoptosis, inflammation, and fibrosis, highlighting that the activation of ER stress-related detrimental pathways could have a role in the cellular damage observed in AFD, in addition to GB3 intra-lysosomal accumulation. The gene discussed is GLA; the disease is Nager acrofacial dysostosis.