rs28371759 — CYP3A4 *18 (L293R)

CYP3A4*18 — A Rare Missense Variant Reshaping Drug Clearance in East Asians

CYP3A4 is the single most consequential drug-metabolizing enzyme in the human body, responsible for the biotransformation of approximately 50% of all prescription medications¹¹ 50% of all prescription medications
The CYP3A subfamily collectively handles more clinical drugs than any other metabolic pathway. Found primarily in the liver and small intestine, CYP3A4 processes everything from immunosuppressants and statins to anticoagulants, antiepileptics, and targeted cancer therapies. When a variant reduces its activity — even modestly — the downstream effects ripple through a large fraction of pharmacological care.

The CYP3A4*18 allele, defined by the rs28371759 polymorphism (c.878T>G on the coding strand; p.Leu293Arg on the protein), substitutes a leucine with the bulkier, charged arginine at position 293. This position sits within a structurally important region of the enzyme, and multiple independent studies associate the variant with reduced catalytic activity²² multiple independent studies associate the variant with reduced catalytic activity
A 2024 systematic review of 23 studies in 2,177 epilepsy patients concluded that CYP3A4 rs28371759 is linked to reduced catalytic activity. The allele is rare globally — found in fewer than 1 in 10,000 European chromosomes — but reaches frequencies of 1–2% in East Asian populations³³ 1–2% in East Asian populations
Particularly elevated in Korean, Japanese, and Han Chinese cohorts, where it carries real clinical relevance.

The Mechanism

CYP3A4 is on the minus (coding) strand of chromosome 7. The c.878T>G change (plus-strand A>G at chr7:99,764,003 GRCh38) replaces leucine-293 with arginine. Leucine is a nonpolar, hydrophobic residue; arginine carries a positive charge and a large side chain. This radical physicochemical substitution is predicted to disrupt local protein folding⁴⁴ disrupt local protein folding
SIFT and PolyPhen-2 classify p.Leu293Arg as damaging/probably damaging in or near the enzyme's substrate-binding and heme-coordinating regions. The functional consequence is reduced intrinsic clearance of CYP3A4 substrates — carriers metabolize affected drugs more slowly than people with the common Leu293 allele.

The Evidence

Clinical evidence for rs28371759 comes primarily from East Asian cohorts, where the allele is most prevalent. A 2017 study of 183 northern Han Chinese patients⁵⁵ 2017 study of 183 northern Han Chinese patients
Liu et al. warfarin dosing study in patients with mechanical heart valve replacement found that CYP3A4 rs28371759 was independently associated with higher warfarin maintenance doses, contributing 2.5% of dose variability in multivariate regression. Since CYP3A4 plays a secondary role in warfarin S-enantiomer metabolism (CYP2C9 is primary), the variant's detection even in this context speaks to its functional impact.

A 2023 cohort study of 63 Thai NSCLC patients⁶⁶ 2023 cohort study of 63 Thai NSCLC patients
Majam et al. retrospective/prospective study of CYP450 polymorphisms and osimertinib outcomes identified rs28371759 among six SNPs significantly increasing adverse drug reaction incidence with osimertinib (a CYP3A4-metabolized EGFR inhibitor). A 2024 systematic review of carbamazepine pharmacogenetics⁷⁷ 2024 systematic review of carbamazepine pharmacogenetics
Riffi et al. 23 studies, 2,177+ epilepsy patients explicitly concluded that rs28371759 contributes to reduced catalytic activity affecting carbamazepine clearance.

Population surveys confirm the East Asian enrichment: Lee et al. 2013⁸⁸ Lee et al. 2013
CYP3A4 and CYP3A5 polymorphism screening across five ethnic groups found the highest minor allele frequency for CYP3A4*18 in the Korean cohort, and a 2024 Sri Lankan pharmacogenomics survey recorded a frequency of ~0.1%, consistent with the near-absence seen in South and European populations. Heart transplant pharmacokinetic models in Chinese cohorts have incorporated this variant as a significant covariate for tacrolimus clearance.

The overall evidence level is moderate: findings are replicated across independent cohorts and multiple drug classes, the biological mechanism is plausible, and the variant is analytically clean (rare, well-characterized missense change). However, no large prospective randomized trials or CPIC/DPWG guidelines exist specifically for this allele.

Practical Actions

For the vast majority of people worldwide, this variant is absent and no action is needed. For carriers — especially those of East Asian ancestry — the implications depend on which CYP3A4-metabolized drugs are prescribed.

For narrow therapeutic index drugs like tacrolimus, cyclosporine, and carbamazepine, reduced CYP3A4 activity means slower clearance: standard doses can produce supratherapeutic blood levels, raising toxicity risk. Therapeutic drug monitoring becomes especially important. For warfarin, the pharmacogenomics team should consider rs28371759 status alongside the dominant CYP2C9 and VKORC1 variants when modeling dose requirements.

The compounding effect of carrying rs28371759 alongside CYP3A4*22 (rs35599367) or CYP3A5*3/*3 (rs776746) is clinically important: these variants converge on the same metabolic pathway, and combined carriers may have substantially greater reductions in total CYP3A clearance than any single variant predicts.

Interactions

CYP3A4 rs28371759 interacts with the CYP3A metabolic axis:

CYP3A4*22 (rs35599367): This established decreased-function allele reduces CYP3A4 mRNA expression ~50%. Carriers of both rs28371759 (reduced protein function) and CYP3A4*22 (reduced protein quantity) would have severely diminished total CYP3A4 capacity. The combined recommendation for tacrolimus dosing should weight the established CYP3A4*22 guideline as primary, with rs28371759 as an additional signal for close monitoring.

CYP3A5*3 (rs776746): CYP3A5 non-expressers (*3/*3) already lack the CYP3A5 backup pathway. An rs28371759 carrier who is also CYP3A5*3/*3 (very common in Europeans) has reduced CYP3A4 activity with no CYP3A5 to compensate — these individuals are at greatest risk of accumulating tacrolimus, cyclosporine, or other CYP3A substrates to toxic levels.

CYP3A4*1G (rs2242480): This intronic variant reduces both CYP3A4 and CYP3A5 expression ~30% and is common in East Asian populations where rs28371759 also reaches actionable frequency. Co-occurrence of both alleles in the same individual would represent additive reductions in CYP3A metabolic capacity.