rs1065852 — CYP2D6 *10

CYP2D6*10 - The Decreased Function Variant

The CYP2D6*10 allele¹¹ rs1065852 is the most common decreased-function variant worldwide. While it is most prevalent in East Asian populations (frequency 40-70%), it is also found at lower frequencies in European populations. Unlike the *4 allele which completely abolishes enzyme function, *10 produces a functional but unstable enzyme with reduced activity.

The Mechanism

The rs1065852 variant causes a proline-to-serine substitution at position 34 of the CYP2D6 protein²² Amino acid change: proline to serine at position 34 (P34S). This amino acid change occurs in the N-terminal signal anchor sequence, affecting how the enzyme is folded and inserted into the endoplasmic reticulum membrane. The resulting enzyme has reduced stability and lower catalytic efficiency, typically retaining about 25-50% of normal activity.

Clinical Impact

Because *10 reduces rather than eliminates activity, its clinical impact is more subtle than *4. However, when combined with another reduced or non-functional allele (like *4), the compound effect can push someone into the poor metabolizer category. For medications with narrow therapeutic windows³³ Narrow therapeutic window: small difference between effective dose and toxic dose, even moderate reductions in CYP2D6 activity can be clinically meaningful. This variant is the most frequently observed decreased-function allele in East Asian populations⁴⁴ most frequently observed decreased-function allele in East Asian populations
Bradford et al. CYP2D6 allele frequency study, 2002, making it a major contributor to the higher prevalence of intermediate metabolizers in these populations.

Combined CYP2D6 Status

Your overall CYP2D6 metabolizer status is determined by the combination of both alleles. Someone carrying *1/*10 (one normal, one decreased) would be an intermediate metabolizer, while someone with *4/*10 (one non-functional, one decreased) would likely be classified as a poor metabolizer. This is why looking at all CYP2D6 variants together is essential for accurate phenotype prediction. The CPIC activity score system⁵⁵ CPIC activity score system
Gaedigk A et al. Clin Pharmacol Ther, 2008 assigns *10 a value of 0.25, compared to 1.0 for the normal *1 allele and 0 for the non-functional *4.

Practical Considerations

If you carry the *10 allele, your CYP2D6 function is moderately reduced. The clinical significance depends on your other CYP2D6 allele and the specific medication in question. For medications with wide therapeutic windows, this may not matter much. For medications like tamoxifen, codeine, or tricyclic antidepressants, even moderate reductions in CYP2D6 activity can affect outcomes.