rs58440431 — CYP2D6

Intronic CYP2D6 variant tagging East Asian *10-lineage suballeles; the C allele co-segregates with reduced-function haplotypes affecting metabolism of ~25% of prescribed medications

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CYP2D6 rs58440431 — The East Asian Suballele Marker

Your genome contains a note at position rs58440431 in the CYP2D6 gene — the enzyme responsible for metabolizing approximately 25% of all prescribed medications, from opioid pain relievers to antidepressants to beta-blockers. This intronic variant, located 90 base pairs into intron 6, does not alter the CYP2D6 protein directly. Instead, it acts as a haplotype tag11 haplotype tag
a haplotype tag is a genetic marker in strong linkage disequilibrium with a functional variant — it travels with the functional variant through generations, reliably marking its presence for specific CYP2D6 suballeles, particularly those of the *10 lineage that dominate drug metabolism variation in East Asian populations.

The Mechanism

CYP2D6 star alleles are defined by sets of variants that co-segregate on the same chromosome. The rs58440431 C allele (plus-strand notation; recorded as c.666+90A>G on the coding strand) co-segregates with *10-lineage suballeles (*10, *36, *39) as well as with certain *4 suballeles. These star alleles span a functional spectrum: CYP2D6*10 retains approximately 25–50% of normal enzyme activity22 CYP2D6*10 retains approximately 25–50% of normal enzyme activity
the *10 Pro34Ser substitution (rs1065852) destabilizes the enzyme in the endoplasmic reticulum membrane, while CYP2D6*36 produces a completely non-functional enzyme33 CYP2D6*36 produces a completely non-functional enzyme
*36 is a rare no-function allele defined in Japanese populations.

The variant itself sits in a region of intron 6 that is in strong linkage disequilibrium with nearby functional changes. Clinical genotyping panels include this position specifically because it improves the accuracy of star allele calling for *10 and related haplotypes — haplotypes that are extremely common in East Asian populations (allele frequency up to 60–68%) but are often underrepresented in genotyping assays designed primarily for European populations.

The Evidence

The clinical relevance of CYP2D6*10 haplotypes — which rs58440431 tags — is well-established. Bradford et al. (2002)44 Bradford et al. (2002)
Bradford LD. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics, 2002 documented that *10 is the dominant reduced-function allele in East Asian populations, present at a median frequency of ~41%, making it the single most important CYP2D6 variant to characterize in these populations. In Korean populations specifically, *10 is the most frequent allele at 46.2%55 46.2%
Lee et al. CYP2D6 allele frequencies in Korean population. Biomed Pharmacother, 2018, with *1/*10 and *10/*10 diplotypes accounting for over half of all observed genotype combinations.

CYP2D6 phenotype has direct consequences for tramadol efficacy. In a population-based pharmacokinetic study, Lam et al. (2007)66 Lam et al. (2007)
Lam YWF et al. Impact of CYP2D6 genetic polymorphism on tramadol pharmacokinetics and pharmacodynamics. J Clin Pharmacol, 2007 found that intermediate metabolizers had 1.3-fold slower tramadol clearance than extensive metabolizers, with the *10 allele present in approximately 40% of the Asian cohort. Reduced clearance translates directly to variable analgesic efficacy and altered adverse effect profiles.

The 2021 joint consensus recommendations for clinical CYP2D6 genotyping77 2021 joint consensus recommendations for clinical CYP2D6 genotyping
Pratt VM et al. Recommendations for Clinical CYP2D6 Genotyping Allele Selection. J Mol Diagn, 2021 explicitly include rs58440431 (recorded as rs2267447) among the core allele-defining SNPs recommended for clinical testing, given its role in accurately identifying *10-lineage haplotypes across multiethnic populations.

Practical Implications

The clinical significance of rs58440431 depends on whether your C allele occurs on a *10, *36, or *39 background — information that requires full haplotype analysis. Without that context, carrying one or two copies of the C allele suggests a meaningful probability of reduced CYP2D6 activity, particularly if you are of East Asian ancestry.

For medications requiring CYP2D6 activation (codeine → morphine; tramadol → O-desmethyltramadol; tamoxifen → endoxifen), reduced activity means reduced therapeutic conversion and potentially inadequate treatment. For medications cleared by CYP2D6 (most antidepressants, some antipsychotics, beta-blockers), reduced activity means drug accumulation and elevated side effect risk.

Interactions

This variant does not act alone. The defining functional variant for *10 is at rs1065852 (Pro34Ser); rs58440431 is an intronic marker that travels with it. Similarly, *36 and *39 suballeles carry additional variants that alter their functional classification. Complete CYP2D6 phenotyping requires assessing all relevant variants on both chromosomes to derive the diplotype and, from that, the predicted metabolizer phenotype. Importantly, drug-drug interactions (phenoconversion) can further reduce CYP2D6 activity — strong inhibitors such as fluoxetine, paroxetine, and bupropion can push intermediate metabolizers into poor metabolizer territory regardless of genotype.

Drug Interactions

codeine reduced_efficacy CPIC
tramadol reduced_efficacy CPIC
tamoxifen reduced_efficacy CPIC
paroxetine dose_adjustment CPIC
fluoxetine dose_adjustment CPIC
venlafaxine dose_adjustment CPIC
nortriptyline dose_adjustment CPIC
amitriptyline dose_adjustment CPIC
atomoxetine dose_adjustment CPIC
metoprolol dose_adjustment DPWG

Genotype Interpretations

What each possible genotype means for this variant.

TT Reference Genotype Normal

No C allele detected; reference genotype at this intronic position

You have two copies of the T allele at rs58440431, which is the GRCh38 reference allele and the most common allele globally. This result means you do not carry the C allele that tags *10-lineage CYP2D6 suballeles prevalent in East Asian populations. About 65% of people globally share this genotype.

Your CYP2D6 metabolizer status is determined by other variants in the gene. This position alone does not indicate reduced enzyme activity.

CT Intermediate Metabolizer Risk Intermediate

One copy of C allele — likely carries a *10-lineage CYP2D6 suballele

The CYP2D6*10 allele (tagged by the C allele at this position) is the most common reduced-function CYP2D6 variant in East Asian populations, with allele frequencies of 40–70% in these groups. Its Pro34Ser substitution destabilizes the enzyme in the endoplasmic reticulum, reducing catalytic activity to roughly 25–50% of normal. CPIC assigns an activity score of 0.25 to *10 (compared to 1.0 for normal *1/*2 alleles).

Full CYP2D6 diplotype assessment — which accounts for both chromosomes and the full haplotype context — is necessary for accurate metabolizer status prediction. Clinical pharmacogenomic panels that sequence or genotype the key *10-defining variants (including rs1065852 for the Pro34Ser change) provide a more complete picture.

CC Poor Metabolizer Risk Decreased

Two copies of C allele — likely carries *10-lineage suballeles on both chromosomes

The *10/*10 diplotype is one of the most common reduced-function CYP2D6 configurations in East Asian populations, present in 22% of Korean subjects in population-based studies. With an CPIC activity score of 0.5 (two × 0.25 for each *10 allele), *10/*10 individuals are classified as intermediate metabolizers — though functionally they metabolize CYP2D6 substrates considerably slower than *1/*1 normal metabolizers.

CYP2D6*36, another allele tagged by the C variant at this position, produces a completely non-functional enzyme. If one chromosome carries *36 and the other *10, the activity score would be 0.25, approaching poor metabolizer territory. Full haplotype resolution — through a clinical CYP2D6 panel — is necessary to distinguish *10/*10 from *36/*10 or *10/*39 configurations.