Other variants in this gene are implicated in causing multiple epiphyseal dysplasia in a dominant manner, but this variant has been seen in several random controls — 2 out of 98 control alleles reported by Czarny-Ratajczak et al. and 3 out of 128 PGP + public genome alleles. Genetests gives the prevalence of this disease as 1 in 10,000, but notes that this is likely an underestimate due to underdiagnosis: http://www.ncbi.nlm.nih.gov/books/NBK1123/ Variants implicated to date have been fully or highly penetrance.
To test the significance of findings in controls, we compare our observations against the predicted allele frequency for a hypothetical variant with moderate (5%) penetrance responsible for half of all cases (1 in 1,000 carriers, 1 in 20,000 affected) — such a variant would have an allele frequency in the general population of .05%. Combining Czarny-Ratajczak et al and PGP + public data, the chances of seeing such a rare variant (with .05% frequency) 5 or more times in 226 alleles is p=1.34*10^-7.