Abstract The recent years have seen a drastic increase in the amount of available genomic sequences. Alongside this explosion, hundreds of computational tools were developed to assess the impact of observed genetic variation. Critical Assessment of Genome Interpretation (CAGI) provides a platform to evaluate the performance of these tools in experimentally relevant contexts. In the CAGI-5 challenge assessing the 38 missense variants affecting the human Pericentriolar material 1 protein (PCM1), our SNAP-based submission was the top performer, although it did worse than expected from other evaluations. Here, we compare the CAGI-5 submissions, and 24 additional commonly used variant effect predictors, to analyze the reasons for this observation. We identified per residue conservation, structural, and functional PCM1 characteristics, which may be responsible. As expected, predictors had a hard time distinguishing effect variants in nonconserved positions. They were also better able to call effect variants in a structurally rich region than in a less-structured one; in the latter, they more often correctly identified benign than effect variants. Curiously, most of the protein was predicted to be functionally robust to mutation—a feature that likely makes it a harder problem for generalized variant effect predictors.