rs28371725 — CYP2D6 *41

CYP2D6*41 — One of the Most Common Intermediate Metabolizer Alleles

The CYP2D6 enzyme metabolizes approximately 25% of all prescribed drugs, including pain medications, antidepressants, antipsychotics, and some cardiovascular drugs.

CYP2D6 is involved in the metabolism of a wide range of medications including drugs for pain management, cancer, mental health disorders, some cardiovascular symptoms . The CYP2D6*41 allele is defined by an intronic variant (2988G>A, also known as c.985+39G>A) that disrupts normal splicing patterns, resulting in increased levels of a nonfunctional splice variant lacking exon 6 and up to 2.9-fold less functional transcript .

CYP2D6*41 has allele frequencies of 4% to 11.5% among individuals of African ancestry, 2% to 12% in Asian populations, and approximately 9% in Europeans .

The allele is particularly prevalent in Arabian Peninsula countries, with frequencies reaching 18.4% in Saudi Arabia and 15.2% in the United Arab Emirates . This makes *41 one of the most common decreased-function CYP2D6 alleles worldwide, contributing to the intermediate metabolizer phenotype in approximately 10-15% of Caucasians ¹¹ carriers typically have one *41 allele paired with a normal-function allele.

The Mechanism

The 2988G>A variant sits in intron 6, 39 base pairs downstream from exon 6.

This intronic change is associated with increased levels of a nonfunctional splice variant lacking exon 6 . The aberrant splicing shifts the balance of transcripts away from the functional full-length mRNA toward a version that cannot produce active enzyme. Studies have shown that

*41 carriers have up to 7.3-fold increased levels of the splice variant and up to 2.9-fold less functional transcript .

Research initially attributed the reduced function of *41 to the R296C amino acid change (which defines the *2 allele that often co-occurs with the intronic variant), but subsequent work demonstrated that rs16947 (R296C) in CYP2D6*2, rather than rs28371725 in CYP2D6*41, reduces CYP2D6 activity via increased non-productive splicing . However, when both variants occur together on the *41 haplotype, the combined effect produces consistent intermediate metabolizer status.

The Evidence

The CPIC guideline assigns the *41 allele an activity score of 0.5, classifying individuals with one *41 allele paired with a normal-function allele as intermediate metabolizers (activity score 1.0) ²² and homozygous *41/*41 individuals as intermediate metabolizers (activity score 1.0). However, real-world pharmacokinetic data reveals important nuances.

CYP2D6*41/*41 carriers exhibit consistently lower metabolism than other genotypes with a guideline score of 1, and show similar or lower metabolic ratios than CYP2D6*10/Null carriers

³³ suggesting the guideline activity score of 0.5 may overestimate *41 function.

Clinical evidence from multiple substrates confirms reduced drug metabolism in *41 carriers. For codeine and tramadol, which require CYP2D6 activation to produce their active metabolites (morphine and O-desmethyltramadol), *41 carriers experience reduced analgesia ⁴⁴ a 2022 pragmatic trial showed CYP2D6-guided opioid prescribing improved pain control in intermediate and poor metabolizers. Conversely, for drugs directly inactivated by CYP2D6 (paroxetine, fluvoxamine, venlafaxine), *41 carriers have higher parent drug concentrations and increased risk of side effects.

A particularly striking case report documented acute dystonic reactions to ondansetron, prochlorperazine, and metoclopramide in a family where the proband was heterozygous for *41 and her father was homozygous *41

⁵⁵ illustrating that even intermediate metabolizer status can have serious clinical consequences.

Practical Implications

If you carry one or two copies of the *41 allele, your CYP2D6 enzyme activity is reduced but not absent. This has bidirectional clinical implications depending on whether the drug is a prodrug requiring activation or a parent drug requiring inactivation.

For prodrugs (codeine, tramadol, tamoxifen): *41 carriers produce less active metabolite, which can lead to treatment failure. CPIC recommends avoiding codeine and tramadol in intermediate metabolizers, or using alternative opioids not metabolized by CYP2D6 (morphine, hydromorphone, oxymorphone, fentanyl) ⁶⁶ as these do not require CYP2D6 activation.

For drugs inactivated by CYP2D6 (most antidepressants, antipsychotics): *41 carriers accumulate higher drug levels. For paroxetine and fluvoxamine, CPIC recommends considering a 50% dose reduction or selecting an alternative SSRI not extensively metabolized by CYP2D6 (sertraline at standard doses, citalopram, escitalopram) ⁷⁷ to minimize risk of side effects from elevated parent drug concentrations.

Drug-drug interactions are particularly important for *41 carriers. Strong CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine) can push an intermediate metabolizer into poor metabolizer territory through phenoconversion ⁸⁸ causing what looks like poor metabolizer status despite having a less severe genotype.

Interactions

CYP2D6 metabolism is determined by the combination of both alleles. Individuals with *41 paired with a no-function allele (*3, *4, *5, *6) typically have activity scores of 0.5 and are classified as intermediate metabolizers, though they may function closer to poor metabolizers for some substrates. When *41 is paired with another decreased-function allele like *10, the combined reduction can significantly impair drug metabolism. Conversely, *41 paired with a gene duplication (*1xN, *2xN) can restore activity closer to normal metabolizer levels.

The *41 haplotype usually contains both rs28371725 (the splice defect) and rs16947 (R296C, defining *2). Some research suggests enhancer variants in linkage disequilibrium with these SNPs can modulate the functional impact ⁹⁹ adding complexity to predicting enzyme activity from genotype alone. This complexity underscores why clinical interpretation requires assessment of the full CYP2D6 diplotype, not single SNPs in isolation.