Recently, proteins originating from presumed null alleles were biochemically characterised as inactive in basal transcription [27], providing an explanation as to why these alleles failed to rescue lethality in haploid S. pombe with a null mutation in the XPD homologue rad15 [19]. Our data suggest that certain presumed null alleles, although unable on their own to support basal transcription, may in fact have a substantial impact on disease outcome in compound heterozygous humans, as they do in mouse models.