Modifier evidence cannot resolve a primary variant classification
Disputed classification: pathogenic versus uncertain significance for variants affecting meiotic segregation.
Natural variation associated with centromere-proximal crossover frequency and segregation distortion may identify modifier loci, while SPF2, SGO2, and CTF18 are described as suppressors of crossovers near centromeres. Neither title establishes that a specific human variant disrupts the relevant mechanism.
What variant-level evidence is available: allele-specific functional data, segregation with aneuploidy, rescue, or evidence that modifier background changes penetrance enough to explain classification disagreement?
