Glycine substitutions, presumed to destabilize the collagen triple helix, are the most common change in X-linked Alport syndrome caused by COL4A5 variants, but have been found less frequently in autosomal recessive Alport syndrome caused by bi-allelic COL4A3 or COL4A4 variants.34, 35, 36, 37 Interestingly, glycine substitutions with arginine, aspartic acid, glutamic acid, tryptophan, or valine have been shown to result in more severe disease compared to substitutions with alanine, serine, or cysteine.38 This evidence concerns the gene COL4A4 and autosomal recessive Alport syndrome.