Melanocytic nevi are the most potent risk factors for melanoma yet identified. 
Variation in the nevus phenotype within a population is predominantly 
genetically determined. Genes that determine nevus expression may therefore act 
as low penetrance melanoma susceptibility genes. Rare germline mutations in 
CDKN2A predispose to melanoma and appear to be nevogenic, although the 
correlation between nevus phenotype and mutation status is poor. It is plausible 
that more common CDKN2A variants may influence both melanoma susceptibility and 
nevus susceptibility. Ala148Thr is a G to A missense polymorphism of CDKN2A, 
which is found in 4%-6% of the general population. We have investigated the role 
of Ala148Thr as a low penetrance melanoma or nevus susceptibility allele in two 
separate groups of individuals. The first was a sample of 488 adults recruited 
from 179 families of patients with the atypical nevus phenotype and/or a family 
history of melanoma, and the second was a population-based sample of 599 women. 
Similar prevalences of Ala148Thr (4.9% and 5.2%) were found in both samples but 
significant variation in the prevalence of the polymorphism was seen across 
geographic areas within England. There was no association between Ala148Thr 
status and nevus number or history of melanoma, and therefore the results did 
not support the hypothesis that the Ala148Thr variant is a low penetrance 
melanoma or nevus susceptibility allele. A significant protective role of 
Ala148Thr on the number of atypical nevi was observed in the family sample (mean 
of 1 atypical nevus in those with the allele and 3.5 nevi in those without, p = 
0.02). After allowing for potential confounders this was not evident in the 
population-based sample.