rs72549354 — CYP2D6 *20

Frameshift insertion creating a null CYP2D6 allele; carriers cannot metabolize ~25% of common drugs including opioids, antidepressants, and antipsychotics

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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.

Drug Interactions

codeine ineffective CPIC
tramadol ineffective CPIC
hydrocodone reduced_efficacy CPIC
tamoxifen reduced_efficacy CPIC
nortriptyline increased_toxicity CPIC
amitriptyline increased_toxicity CPIC
desipramine increased_toxicity CPIC
imipramine increased_toxicity CPIC
clomipramine increased_toxicity CPIC
doxepin increased_toxicity CPIC
paroxetine increased_toxicity CPIC
fluvoxamine increased_toxicity CPIC
venlafaxine increased_toxicity CPIC
atomoxetine increased_toxicity CPIC
ondansetron reduced_efficacy CPIC
tropisetron reduced_efficacy CPIC
metoprolol increased_toxicity DPWG
propafenone increased_toxicity DPWG
eliglustat increased_toxicity CPIC
thioridazine contraindicated FDA

Genotype Interpretations

What each possible genotype means for this variant.

II Normal Metabolizer Normal

Normal CYP2D6 function — no *20 allele detected

You do not carry the CYP2D6*20 frameshift insertion. This is the typical result — the *20 allele is extremely rare (observed in approximately 1 in 40,000 chromosomes in Japanese populations) and has not been detected at measurable frequency in most ancestry groups. Your CYP2D6 metabolizer status is not affected by this variant, though other CYP2D6 variants may still influence your overall enzyme activity.

DI Intermediate Metabolizer Intermediate

One copy of CYP2D6*20 — reduced drug metabolism

With one non-functional *20 allele, your CYP2D6 enzyme output is reduced by roughly half (assuming the other allele is normal). For prodrugs like codeine and tramadol that require CYP2D6 to generate active metabolites, you will have diminished pain relief. For drugs that are eliminated by CYP2D6, you will accumulate slightly higher drug concentrations, increasing risk of dose-dependent side effects.

Critically, strong CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine) can push your remaining functional allele toward zero activity through phenoconversion, effectively converting you to a poor metabolizer phenotype. This risk is particularly relevant when combining multiple CYP2D6 substrates or inhibitors.

DD Poor Metabolizer Absent

Two copies of CYP2D6*20 — no enzyme function

With no functional CYP2D6 enzyme, your body cannot metabolize any drug that depends on this pathway. This affects two distinct classes of drugs in opposite ways: prodrugs that require CYP2D6 for activation will have no effect, while drugs that are inactivated by CYP2D6 will accumulate to toxic levels. Every prescribing physician and pharmacist who treats you needs this information. Formal pharmacogenomics documentation — such as a wallet card or annotated medical record — can prevent dangerous prescribing decisions in emergency or unfamiliar clinical settings.

Given the extreme rarity of homozygous *20, confirmation of this result by clinical-grade CYP2D6 sequencing is warranted before acting on it.