rs71328650 — CYP2D6

Intronic CYP2D6 haplotype tag variant (rs28371702 canonical form) associated with altered drug metabolism ratios for CYP2D6 substrates including aripiprazole and praziquantel

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CYP2D6 rs71328650 — An Intronic Haplotype Tag with Emerging Drug Metabolism Evidence

CYP2D6 is responsible for metabolizing approximately 20–25% of all clinically prescribed medications, including opioids, antidepressants, antipsychotics, and beta-blockers. Most clinically significant CYP2D6 variants are defined by named star alleles — 4 (the most common null allele), *10 (reduced function), *6 (frameshift), and *41 (splice-impaired). rs71328650 is the legacy identifier for what is now catalogued in dbSNP as **rs28371702*, an intronic variant at position c.181-41 in the CYP2D6 gene. Understanding this variant requires distinguishing between its independent functional significance and its role as a haplotype tag.

The Mechanism

The rs71328650/rs28371702 A>C variant lies in intron 1 of CYP2D6, 41 bases upstream of exon 2 (c.181-41). CYP2D6 is encoded on the minus strand of chromosome 22; the plus-strand reference allele at GRCh38 position 42,129,950 is A, corresponding to a T on the coding strand[| Minus-strand genes: the genomic plus strand runs 5'-to-3' in the opposite direction from the coding sequence. What genome files report as A at this position is T in the mRNA/protein coding context]. The alternate C allele on the plus strand corresponds to G on the coding strand, placing it at c.181-41T>G in HGVS notation.

Importantly, this intronic position is not the c.985+39G>A (2988G>A) causal variant that defines CYP2D6*41[| CYP2D6*41 is defined by a different intronic SNP — c.985+39G>A — which causes aberrant exon 6 splicing]. The *41 variant lies in intron 6, not intron 1, and is mechanistically characterized as increasing nonfunctional splice variants lacking exon 6 by up to 7.3-fold11 7.3-fold
Toscano C et al. Pharmacogenet Genomics, 2006. rs28371702 does not have a published equivalent mechanistic study demonstrating a specific splicing effect at the c.181-41 position.

The Evidence

Two published studies have associated rs28371702 with CYP2D6 drug metabolism outcomes:

In a 2025 pediatric study of aripiprazole pharmacokinetics22 Xin Y et al. BMC Pediatr, 2025, rs28371702 was among six CYP2D6 variants where the steady-state metabolic ratio (AUC-based) was significantly associated with rs28371702 genotype, suggesting this intronic variant tags a haplotype affecting how aripiprazole is cleared. Aripiprazole is a partial dopamine agonist metabolized primarily by CYP2D6 and CYP3A4, and its active metabolite (dehydro-aripiprazole) accumulates differently depending on CYP2D6 activity.

In a 2022 African study of praziquantel treatment for schistosomiasis33 Zdesenko G et al. Front Genet, 2022, the rs28371702 CC genotype was the sole CYP2D6 variant significantly associated with treatment failure (odds ratio 2.36, p = 0.024). Praziquantel is primarily metabolized by CYP3A4, but CYP2D6 contributes to its biotransformation; this finding suggests the CC haplotype may tag a reduced-function CYP2D6 background in African populations, where the C allele frequency reaches ~64%.

Neither study provides direct mechanistic evidence that the intronic c.181-41 position itself causes functional change — the most parsimonious interpretation is that rs28371702 serves as a linkage disequilibrium tag for one or more functional CYP2D6 variants that have not been fully resolved in the haplotype structure. Evidence quality is emerging — two independent association signals without mechanistic characterization.

Practical Actions

The clinical actionability of rs28371702 alone is limited by the absence of CPIC or DPWG guideline designations. If you carry one or two C alleles at this position, the most important step is ensuring your overall CYP2D6 phenotype has been assessed through the complete set of characterized star alleles (*2, *4, *6, *10, *41), since the Gaedigk activity score44 Gaedigk A et al. CYP2D6 activity score. Clin Pharmacol Ther, 2008 summarizes cumulative CYP2D6 function across all haplotypes. Isolated interpretation of rs28371702 without the full haplotype context may be misleading.

Interactions

CYP2D6 function is determined by the combined activity score of both alleles. The clinically characterized variants in the platform — rs3892097 (*4), rs1065852 (*10), rs16947 (*2), rs28371725 (*6), and rs5030655 (*3) — each have established activity scores and CPIC/DPWG guideline support. rs71328650/rs28371702 does not yet have an activity score assignment. In populations where the C allele is common (African, East Asian), this variant may co-segregate with reduced-function haplotypes that are not fully captured by the European-derived star allele panel — an important consideration for ancestry-aware pharmacogenomics.

Drug Interactions

aripiprazole dose_adjustment literature
praziquantel reduced_efficacy literature

Genotype Interpretations

What each possible genotype means for this variant.

AA Reference Genotype Normal

GRCh38 reference genotype — no additional CYP2D6 impairment from this position

You carry the GRCh38 reference allele (A) at both copies of this intronic CYP2D6 position. The A allele is less common globally (~40%) but is the major allele in South Asian (~85%) and Latino (~94%) populations. No published study identifies AA homozygotes as having altered CYP2D6 activity at this locus. Your overall CYP2D6 drug metabolism status is determined by the established star alleles catalogued at other positions in your profile.

AC Heterozygous Carrier Intermediate

One C allele at this CYP2D6 intronic position

In the aripiprazole pharmacokinetics study (Xin et al., 2025, PMID 40598106), rs28371702 was among the CYP2D6 variants associated with steady-state metabolic ratios in children receiving aripiprazole. The specific magnitude of effect for AC heterozygotes was not separately reported in the abstract. The heterozygous state likely produces an intermediate signal compared to CC homozygotes, consistent with codominant inheritance typical of CYP2D6 haplotype effects.

CC Homozygous Alternate Decreased

Homozygous C allele — associated with altered CYP2D6 substrate metabolism

The praziquantel association (PMID 35754834) is particularly notable because rs28371702 was the sole statistically significant CYP2D6 variant among those tested, with a more than two-fold increase in odds of treatment failure in CC carriers (OR 2.36, p = 0.024). Praziquantel (PZQ) is predominantly metabolized by CYP3A4, but CYP2D6 contributes to its biotransformation to 4-OH-praziquantel. Reduced CYP2D6 activity could alter PZQ pharmacokinetics, potentially reducing plasma exposure at the site of action.

For aripiprazole, a second-generation antipsychotic with a narrow therapeutic window[| Narrow therapeutic window: small gap between effective and toxic plasma concentrations], CYP2D6 genotype is already included in FDA labeling as a pharmacogenomic biomarker. The contribution of rs28371702 to aripiprazole exposure in the 2025 study (PMID 40598106) adds to the evidence that this intronic tag carries functional information beyond linkage disequilibrium alone.

Because the underlying functional mechanism at c.181-41 is not established, it is possible that rs28371702 tags a more functionally significant variant in strong LD — one not captured by the standard European-derived star allele panel. This interpretation is consistent with the African population context of the praziquantel study.