CYP2D6 *10

CYP2D6*10 - The Decreased Function Variant

The CYP2D6*10 allele| 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 protein| 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 windows| 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 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 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.