rs72549354 — CYP2D6 *20

CYP2D6*20 — A Rare Null Allele That Silences Drug Metabolism

CYP2D6 is one of the most pharmacologically important enzymes in the human body, responsible for metabolizing approximately 25% of all commonly prescribed drugs — spanning psychiatry, oncology, pain management, and cardiology. The CYP2D6*20 allele¹¹ CYP2D6*20 allele
rs72549354, c.635dup on chromosome 22 is a rare null allele defined by a single-cytosine duplication that completely destroys enzyme function. Carriers of one or two copies of *20 are classified as poor or intermediate metabolizers and should have CYP2D6 substrate medications reviewed carefully.

The Mechanism

The *20 variant results from a duplication of a cytosine residue within exon 5 of the CYP2D6 coding sequence ²² NC_000022.11:g.42128817dup; NM_000106.6:c.635dup. This frameshift disrupts the reading frame from codon 213 onward, producing a severely truncated protein (p.Leu213fs) that lacks the catalytic heme-binding domain essential for enzyme activity. The resulting protein has zero enzymatic function — there is no partial activity from this allele.

³³ Unlike reduced-function alleles such as *10 (rs1065852) or *41 (rs28371725), which retain some enzyme capacity, *20 behaves identically to the deletion allele *6 (rs5030655): complete null. In the CPIC activity score system, *20 is assigned an activity value of 0, identical to *3, *4, *5, *6, and other established no-function alleles.

The Evidence

CYP2D6 pharmacogenomics has the strongest evidence base of any pharmacogene. The activity score framework⁴⁴ The activity score framework
Gaedigk et al., Clin Pharmacol Ther 2008 enables standardized phenotype assignment: each allele is assigned a value (0 for no function, 0.5 for reduced function, 1.0 for normal function), and the diplotype sum determines metabolizer class.

CYP2D6*20 is extremely rare. Population frequency data are available only from a large Japanese cohort (38KJPN), where the insertion was observed in 2 of 77,224 chromosomes (~0.003%). The allele has not been detected in gnomAD at appreciable frequency in any ancestry group. Despite its rarity, the null consequence of carrying *20 is unambiguous: a person who inherits *20 alongside another no-function or reduced-function allele is a poor metabolizer or an intermediate metabolizer respectively, with the same clinical implications as carriers of the more common null alleles *4 or *6.

CPIC has published Level A guidelines for codeine and tramadol⁵⁵ Level A guidelines for codeine and tramadol
Crews et al., Clin Pharmacol Ther 2021 recommending that poor metabolizers avoid these prodrugs entirely, as CYP2D6 is required to convert them to their active forms. The same evidence base extends to tricyclic antidepressants ⁶⁶ Hicks et al., Clin Pharmacol Ther 2017, SSRIs and SNRIs ⁷⁷ Bousman et al., Clin Pharmacol Ther 2023, and tamoxifen ⁸⁸ Goetz et al., Clin Pharmacol Ther 2018.

Practical Implications

Carrying one copy of *20 paired with a normal-function allele reduces your activity score to 1.0, placing you in the intermediate metabolizer category. Paired with another no-function allele (*4, *6, *3), you are a poor metabolizer with an activity score of 0. The practical consequences differ by drug class:

Prodrugs requiring CYP2D6 activation (codeine → morphine; tramadol → O-desmethyltramadol): neither produces adequate analgesia in poor metabolizers. This is not a dose issue — no amount of the drug will work. Alternative opioids not requiring CYP2D6 (morphine, oxymorphone, hydromorphone, fentanyl, buprenorphine) should be used instead.

Active drugs inactivated by CYP2D6 (most antidepressants, many antipsychotics): poor metabolizers accumulate parent drug to toxic levels even at standard doses. This manifests as exaggerated side effects — nausea, agitation, cardiac effects — rather than lack of efficacy.

Tamoxifen: requires CYP2D6 to generate its active metabolite endoxifen. Poor metabolizers have significantly lower endoxifen levels and potentially inferior breast cancer outcomes. Aromatase inhibitors may be preferable in postmenopausal women.

Interactions

CYP2D6 metabolizer status is determined by the diplotype — both alleles together. CYP2D6*20 (activity score 0) combined with other alleles: - *20 + *1 or *2 → intermediate metabolizer (activity score 1.0) - *20 + *41 → intermediate metabolizer (activity score 0.5) - *20 + *10 → intermediate metabolizer (activity score 0.5) - *20 + *4, *6, *3, or *5 → poor metabolizer (activity score 0)

Additionally, strong CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine) can cause phenoconversion — pushing an intermediate metabolizer into poor metabolizer territory. For *20 heterozygotes, this risk is heightened because there is only one functional allele remaining to be inhibited.

The full CYP2D6 diplotype matters more than any single variant. Clinical pharmacogenomic testing that sequences the entire CYP2D6 locus provides the most complete picture of metabolizer status.