rs3892097 — CYP2D6 *4

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 G>A 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 (AA) 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.