CYP2D6 *4 (rs3892097)

rs3892097 — CYP2D6 *4

CYP2D6 *4 splice-defect null allele — the most common loss-of-function CYP2D6 variant in Europeans (~20% allele frequency) and the most-prescribed-against PGx variant worldwide. Determines codeine and tramadol failure (no morphine/O-desmethyltramadol conversion), reduced tamoxifen→endoxifen activation, and elevated exposure to many SSRIs and tricyclic antidepressants metabolized by CYP2D6.

Population Frequency

72%

25%

CYP2D6*4 - The Most Important Drug Metabolism Gene

CYP2D6 is one of the most clinically significant drug-metabolizing enzymes in the human body. Despite making up only about 2% of liver CYP450 content, it metabolizes approximately 25% of all clinically used medications. The *4 allele¹¹ rs3892097 is the most common non-functional variant in European populations, carried by about 25% of people.

The Mechanism

The CYP2D6*4 variant is a splice site mutation²² A splice site mutation disrupts the boundary between coding and non-coding DNA, preventing correct protein assembly³³ C>T on the plus strand (historically called G1846A on the coding strand) at the intron 3/exon 4 boundary that causes aberrant mRNA splicing, producing a completely non-functional enzyme. Unlike variants that merely reduce activity, *4 abolishes CYP2D6 function entirely from that allele. Individuals homozygous for *4 (TT) are classified as CYP2D6 poor metabolizers.

Prodrugs vs. Active Drugs

The clinical impact of CYP2D6 status depends on whether a medication is a prodrug⁴⁴ A prodrug is inactive until the body converts it to its active form or an active drug (needs CYP2D6 to be eliminated).

For prodrugs like codeine and tramadol, poor metabolizers get NO pain relief because these drugs cannot be converted to their active forms⁵⁵ Codeine is converted to morphine; tramadol to O-desmethyltramadol. This is not a matter of dose adjustment - these drugs simply will not work.

For active drugs like many antidepressants⁶⁶ e.g. fluoxetine, paroxetine, venlafaxine, beta-blockers, and tamoxifen, poor metabolizers accumulate higher drug levels, increasing the risk of side effects and toxicity.

The Evidence

CYP2D6 pharmacogenomics has the strongest evidence base of any pharmacogene. The Clinical Pharmacogenetics Implementation Consortium (CPIC)⁷⁷ Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG)⁸⁸ Dutch Pharmacogenetics Working Group (DPWG)
Dutch Pharmacogenetics Working Group at PharmGKB have published dosing guidelines for over 30 CYP2D6 substrate medications. Major medical centers now routinely test CYP2D6 before prescribing certain medications. The Gaedigk activity score system⁹⁹ Gaedigk activity score system
Gaedigk A et al. The CYP2D6 activity score. Clin Pharmacol Ther, 2008 translates complex CYP2D6 genotypes into a quantitative measure of predicted enzyme activity, enabling standardized phenotype assignment.

What You Should Do

If you carry even one *4 allele, this is clinically actionable information. Share your CYP2D6 status with all prescribing physicians and pharmacists. Consider requesting your full CYP2D6 genotype through clinical pharmacogenomic testing, as 23andMe only captures some of the known variants.

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

trimipramine increased_toxicity CPIC

fluoxetine increased_toxicity CPIC

paroxetine increased_toxicity CPIC

fluvoxamine increased_toxicity CPIC

venlafaxine dose_adjustment CPIC

atomoxetine increased_toxicity CPIC

ondansetron reduced_efficacy CPIC

tropisetron reduced_efficacy CPIC

metoprolol increased_toxicity DPWG

propafenone increased_toxicity DPWG

flecainide increased_toxicity DPWG

eliglustat increased_toxicity CPIC

pimozide increased_toxicity FDA

thioridazine contraindicated FDA

Genotype Interpretations

What each possible genotype means for this variant.

GG Normal Metabolizer Normal

Normal CYP2D6 activity

You have normal CYP2D6 enzyme activity. This enzyme metabolizes about 25% of all medications, including many antidepressants, opioids like codeine and tramadol, and beta-blockers like metoprolol. About 72% of people of European descent share this genotype.

With normal activity, standard doses of these medications should work as expected for you.

CC Normal Metabolizer Normal

Normal CYP2D6 activity

With normal activity, standard doses of these medications should work as expected for you.

AG Intermediate Metabolizer Intermediate

Intermediate CYP2D6 metabolizer

You carry one copy of the CYP2D6*4 variant, which gives you intermediate enzyme activity. About 25% of Europeans share this genotype. This affects how you process about 25% of medications.

For codeine and tramadol, you may get somewhat reduced pain relief since these prodrugs need CYP2D6 to convert them to their active forms.

For drugs that are inactivated by CYP2D6 (like some antidepressants), they may build up slightly more in your system.

CT Intermediate Metabolizer Intermediate

Intermediate CYP2D6 metabolizer

You carry one copy of the CYP2D6*4 variant, which gives you intermediate enzyme activity. About 25% of Europeans share this genotype. This affects how you process about 25% of medications.

For codeine and tramadol, you may get somewhat reduced pain relief since these prodrugs need CYP2D6 to convert them to their active forms.

For drugs that are inactivated by CYP2D6 (like some antidepressants), they may build up slightly more in your system.

AA Poor Metabolizer Poor

Poor CYP2D6 metabolizer - medication adjustments needed

You are a CYP2D6 poor metabolizer. About 3% of Europeans share this genotype. This significantly affects how you process about 25% of medications.

Codeine and tramadol will be INEFFECTIVE for pain relief because you cannot convert them to their active forms. Use alternative pain medications.

Drugs inactivated by CYP2D6 (many antidepressants, metoprolol, tamoxifen) will accumulate in your system, increasing side effects.

TT Poor Metabolizer Poor

Poor CYP2D6 metabolizer - medication adjustments needed

You are a CYP2D6 poor metabolizer. About 3% of Europeans share this genotype. This significantly affects how you process about 25% of medications.

Codeine and tramadol will be INEFFECTIVE for pain relief because you cannot convert them to their active forms. Use alternative pain medications.

Drugs inactivated by CYP2D6 (many antidepressants, metoprolol, tamoxifen) will accumulate in your system, increasing side effects.