CYP2D6 *17

CYP2D6*17 — The African-Ancestry Reduced Metabolizer Allele

CYP2D6 is the body's workhorse for metabolizing about 25% of all
clinical medications — antidepressants, antipsychotics, opioid analgesics,
and the breast cancer drug tamoxifen among them. The *17 allele
| rs28371706, defining the CYP2D6*17 haplotype together with p.Cys296Arg and p.Ser486Thr
is the most clinically significant reduced-function variant in populations of
sub-Saharan African ancestry, where it occurs in roughly 16% of alleles
compared to under 0.3% in Europeans.

The Mechanism

The CYP2D6*17 haplotype carries three coding changes; the defining missense
is p.Thr107Ile | threonine-to-isoleucine substitution at residue 107 of the
CYP2D6 protein. This substitution
lies in the substrate recognition region of the enzyme and reduces catalytic
efficiency without completely abolishing function. The *17 enzyme is present
in normal amounts but processes its substrates more slowly. In the
CPIC activity score system | Gaedigk A et al. Clin Pharmacol Ther, 2008,
the *17 allele is assigned a value of 0.5 — half that of the normal *1 allele
(1.0) and above the non-functional *4 allele (0.0). A diplotype of *1/*17
yields a total score of 1.5 (intermediate metabolizer), while *17/*17 gives
1.0 — still classified as intermediate but at the lower end.

The Evidence

A pharmacokinetics study of 42 healthy Black Zimbabweans by
Kanji et al. | Pharmacokinetics of Tamoxifen and Its Major Metabolites and the Effect of
the African Ancestry Specific CYP2D6*17 Variant. J Pers Med, 2023
found that individuals homozygous for CYP2D6*17 had a 5-fold lower maximum
concentration (Cmax) of endoxifen — the active metabolite of tamoxifen
that suppresses estrogen receptor-positive breast cancer — compared to
heterozygous carriers (who showed a 2-fold reduction). A separate study by
Marasanapalle et al. | Differences in pharmacokinetics of desipramine and dextromethorphan in
African subjects carrying CYP2D6*17 and *29. J Clin Pharmacol, 2024
showed CYP2D6*17 homozygotes were 5-10× slower at metabolizing both
desipramine (a tricyclic antidepressant) and dextromethorphan (a CYP2D6
probe drug), confirming clinically meaningful impairment. In Zimbabwe,
Mapira et al. | CYP2D6*17 frequency of 15.9% in Zimbabwean sickle cell disease patients.
Pharmacogenomics, 2023 found
CYP2D6*17 at a 15.9% allele frequency in sickle cell disease patients
— a population for whom opioid analgesics are frequently prescribed.

A 2025 study of 208 African risperidone users by
Kehinde et al. | CYP2D6 *17 and *29 Allele Activity for Risperidone Metabolism.
Clin Pharmacol Ther, 2025
highlighted a complication: the *17 allele's activity appears substrate-specific,
meaning its functional impact differs depending on which drug is being metabolized.
For risperidone, *17 carriers did not fit neatly into the intermediate metabolizer
bucket predicted by the standard activity score. This underscores the importance
of population-specific, drug-specific pharmacogenomic research for *17 carriers.

Practical Implications

For carriers of one or two *17 alleles, several CPIC-guideline-covered drugs
are directly affected. The CPIC tamoxifen guideline | Goetz MP et al. CPIC Guideline for
CYP2D6 and Tamoxifen Therapy. Clin Pharmacol Ther, 2018
recommends that intermediate metabolizers consider dose escalation to 40 mg/day
(from the standard 20 mg/day) to achieve endoxifen levels sufficient for
breast cancer suppression. For opioids, the CPIC opioid guideline | Crews KR et al.
CPIC Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy.
Clin Pharmacol Ther, 2021 notes
that codeine and tramadol may provide reduced efficacy in intermediate metabolizers.

Interactions

CYP2D6 phenotype is determined by the combined diplotype across both alleles.
A person carrying one *17 allele and one *4 allele (rs3892097) — a non-functional
allele common in Europeans — would have an activity score of 0.5 + 0.0 = 0.5,
placing them in the poor metabolizer range where CPIC recommends avoiding
codeine and tramadol entirely. The combination of *17 with *10 (rs1065852, common
in East Asian populations) gives 0.5 + 0.25 = 0.75, still intermediate but
lower-functioning than *17 alone. Since genome-wide testing may capture each
variant independently, the clinical phenotype depends on reading all CYP2D6
markers together through a formal diplotype report.