rs28371733 — CYP2D6

CYP2D6 Glu418Ter — A Rare Stop-Gain That Silences the Enzyme Completely

The CYP2D6 enzyme handles roughly 25% of all prescribed medications, including opioid pain relievers, antidepressants, antipsychotics, and the breast cancer drug tamoxifen. Most people carry at least one functional copy of CYP2D6, but a small subset carry rare variants that prevent any enzyme from being made at all. rs28371733 is one such variant — a stop-gain mutation¹¹ stop-gain mutation
also called a nonsense mutation; the codon change creates a premature termination signal that truncates the CYP2D6 protein before it can fold into a working enzyme.

This variant is most prevalent in people of African ancestry (allele frequency ~0.86%), where it is approximately 90 times more common than in Europeans (<0.01%). This ancestry-skewed distribution means that African-descent patients are disproportionately at risk of being unrecognised poor metabolisers — a gap that matters enormously when codeine, tramadol, or psychiatric medications are prescribed without pharmacogenomic testing.

The Mechanism

rs28371733 introduces a T at genomic position chr22:42,126,914 (GRCh38) on the plus strand. Because CYP2D6 is transcribed from the minus strand, this corresponds to a c.1252G>T change in the coding sequence (NM_000106.6), converting codon 418 from GAA (glutamic acid) to TAA (stop). The result is a premature termination codon²² premature termination codon
the ribosome reaches the stop signal at position 418 and releases an incomplete 417-amino-acid peptide, which is rapidly degraded rather than folding into active enzyme. With no functional enzyme produced, CYP2D6 activity score is 0.

This is mechanistically distinct from the more common decreased-function alleles (*10, *41) — those reduce enzyme output gradually through splicing or altered catalytic rate. A stop-gain abolishes output entirely. Carriers of this variant on one allele paired with another no-function allele (such as *4 or *6) are classified as CYP2D6 poor metabolizers³³ CYP2D6 poor metabolizers
activity score = 0; the CPIC standard phenotype assignment for individuals whose combined CYP2D6 activity across both alleles equals zero.

The Evidence

The 2021 CPIC guideline for CYP2D6 and opioids⁴⁴ CPIC guideline for CYP2D6 and opioids
Clinical Pharmacogenetics Implementation Consortium — the authoritative body that translates pharmacogenomic evidence into clinical dosing guidance provides strong-level recommendations for CYP2D6 poor metabolizers: avoid codeine and tramadol because both are prodrugs requiring CYP2D6 to produce their active analgesic metabolites (morphine and O-desmethyltramadol, respectively). A poor metabolizer cannot complete this conversion, resulting in treatment failure rather than analgesia.

For antidepressants and antipsychotics, the 2015 CPIC SSRI guideline⁵⁵ 2015 CPIC SSRI guideline
covers fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline; updated recommendations available at PharmGKB recommends selecting alternative drugs not predominantly metabolized by CYP2D6, or reducing standard starting doses by 50% and titrating slowly, for poor metabolizers. Drugs like paroxetine, fluvoxamine, and atomoxetine accumulate to toxic levels without CYP2D6 clearance.

Population-level studies confirm the clinical relevance: a systematic review of 172 studies across 44,572 individuals⁶⁶ 172 studies across 44,572 individuals
Llerena et al. 2015 established that CYP2D6 no-function allele frequency varies substantially by ancestry, underscoring the need for ancestry-aware pharmacogenomic testing. African and admixed populations carry a distinct profile of no-function alleles compared to Europeans, meaning European-biased genotyping panels may miss relevant variants in these groups.

Practical Implications

If you carry the T allele at rs28371733 paired with another no-function CYP2D6 allele, your combined CYP2D6 activity score is 0, placing you in the poor metabolizer category. All CYP2D6 prodrugs (codeine, tramadol) are ineffective for pain relief. All drugs cleared by CYP2D6 (most antidepressants, antipsychotics, atomoxetine, tamoxifen, metoprolol) will accumulate to higher-than-expected levels, increasing side effect and toxicity risk.

The key clinical action is to inform every prescriber of your CYP2D6 status. Emergency settings are the highest-risk environment, because codeine and tramadol are frequently prescribed reflexively for acute pain. Alternative opioids — morphine, hydromorphone, oxymorphone, fentanyl — do not require CYP2D6 activation and are appropriate substitutes.

Interactions

CYP2D6 metabolizer status is determined by the combination of both alleles (the diplotype). A single T allele at rs28371733 paired with a normal-function allele results in intermediate or normal metabolizer status depending on what the other allele contributes. Only when paired with another no-function allele (rs3892097 /*4, rs1065852 /*6, rs5030655 /*3, or gene deletion /*5) does poor metabolizer status result.

Phenoconversion is also relevant: strong CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine) can further suppress residual enzyme activity. For a heterozygous carrier who is already an intermediate metabolizer, adding a CYP2D6 inhibitor can mimic poor metabolizer pharmacokinetics even without a second no-function allele.