Human ribonucleoprotein hnRNPA2 belongs to the set of proteins that bind and shuttle RNA and also contain low-complexity domains (LCDs) having a limited repertoire of amino acid types. These LCDs aggregate into amyloid-like fibrils during the performance of their functions in phase separation. In previous work we determined the cryo-EM structure of the LCD of the wildtype hnRNPA2, finding an amyloid-like fibril that forms a reversible hydrogel. Here we determine the cryo-EM structures of three polymorphic amyloid fibrils formed by the recombinant D290V variant of hnRNPA2 LCD found in patients afflicted with MultiSystem Proteinopathy. In contrast to the wildtype, reversible fibrils, the variant fibrils are irreversible and more stable as judged by phase separation, thermal stability, and energetic calculations. Also, the PY-nuclear localization signal is masked in the fibril cores of all three variant polymorphs, thus rendering it inaccessible to chaperones for RNA trafficking and thereby interfering with function. These findings suggest how a single missense mutation converts functional amyloid-like fibrils to irreversible pathogenic amyloid.