rs55785340 — CYP3A4 *2

CYP3A4*2 — A Rare but Functionally Altered Enzyme Variant

CYP3A4 is the most important drug-metabolizing enzyme in the human body, responsible for the first-pass and systemic clearance of approximately 50% of all prescribed medications. When you swallow a statin, an immunosuppressant, or a benzodiazepine, CYP3A4 in your liver and intestinal wall is the primary enzyme that breaks it down before it reaches your bloodstream. A genetic variant that impairs this enzyme — even modestly — can therefore have significant consequences for how drugs behave in your body.

rs55785340, also known as CYP3A4*2, is a missense variant¹¹ missense variant
A mutation that changes a single amino acid in the protein sequence that substitutes proline for serine at position 222 of the CYP3A4 protein (p.Ser222Pro). It is rare globally — found almost exclusively in Europeans at an allele frequency of roughly 0.07% in large population databases — but its functional impact on nifedipine metabolism is well-documented in vitro, and a large pharmacokinetic study has now confirmed its clinical relevance for statin dosing.

The Mechanism

CYP3A4 catalyzes oxidative reactions by threading drug molecules into its active site, where an oxygen atom is transferred. Serine 222 sits in a substrate-recognition region of the enzyme. The Ser222Pro substitution replaces a flexible serine residue with a rigid proline, which is known to restrict backbone flexibility and alter local protein conformation. The resulting structural change affects how well the enzyme binds and processes certain substrates.

The original characterization by Sata et al. (2000)²² Sata et al. (2000)
Sata F, Sapone A, Elizondo G et al. CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12. Clin Pharmacol Ther 67:48-56 expressed the CYP3A4*2 enzyme in baculovirus and directly measured catalytic activity. The key finding was substrate-dependent impairment³³ substrate-dependent impairment
The CYP3A4*2 variant is a partial loss-of-function, not a complete null — its effect differs depending on which drug enters the active site: nifedipine oxidation showed reduced intrinsic clearance compared to wild-type, while testosterone 6β-hydroxylation was not significantly different. This substrate selectivity matters clinically because it means some CYP3A4 drugs are more affected than others.

The Evidence

The most clinically relevant evidence comes from a genomewide association study of simvastatin pharmacokinetics⁴⁴ genomewide association study of simvastatin pharmacokinetics
Mykkänen AJH et al. Genomewide Association Study of Simvastatin Pharmacokinetics. Clin Pharmacol Ther 2022;112(3):676-686 in 229 Finnish volunteers. Carriers of CYP3A4*2 or CYP3A4*22 (the more common *22 splice variant) showed 87% (90% CI, 39–152%) larger simvastatin acid AUC⁵⁵ AUC
Area under the concentration-time curve, the standard pharmacokinetic measure of total drug exposure than normal metabolizers (P=6.4×10⁻⁴). Because the study grouped *2 and *22 carriers together as "intermediate CYP3A4 metabolizers," the effect size specifically attributable to *2 is not isolated, but the direction is clear: heterozygous carriers are exposed to substantially more simvastatin acid per dose.

The mechanism explains this finding: simvastatin (as the acid form) is a CYP3A4 substrate, and with reduced enzyme activity, less drug is cleared on first pass through the intestinal wall and liver. The result is higher plasma concentrations per dose — the same pharmacokinetic principle that underlies the dangerous interactions between statins and CYP3A4 inhibitors like clarithromycin or grapefruit juice.

Population data from ExAC and 1000 Genomes⁶⁶ ExAC and 1000 Genomes
Large-scale sequencing consortia aggregating hundreds of thousands of samples confirms the variant is nearly absent outside European populations. Of 121,010 alleles in ExAC, only 104 carried the G allele (0.086%), and all occurrences were in non-African, non-East-Asian participants. The FINRISK Finnish cohort showed a slightly higher rate (~1%), consistent with population-specific enrichment in Northern Europe.

Practical Actions

For carriers of CYP3A4*2, the most directly actionable implication is statin safety. Statins metabolized by CYP3A4 — primarily simvastatin, lovastatin, and atorvastatin — will reach higher plasma concentrations per dose. High statin exposure raises the risk of myopathy and rhabdomyolysis⁷⁷ myopathy and rhabdomyolysis
Muscle inflammation and, in severe cases, breakdown of muscle tissue that can cause kidney failure (1-in-10,000 risk with standard doses). Pravastatin, rosuvastatin, and fluvastatin are largely independent of CYP3A4 and are not affected by this variant.

For immunosuppressants (tacrolimus, cyclosporine) after organ transplantation, reduced CYP3A4 activity would theoretically raise drug exposure and increase toxicity risk. However, because CYP3A4*2 is so rare, clinical guidelines have not been developed for it specifically — clinicians rely on therapeutic drug monitoring as standard of care for these drugs regardless of genotype.

There are currently no CPIC or DPWG guidelines specific to CYP3A4*2. Clinical pharmacogenomics testing panels that include CYP3A4 most commonly genotype for CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746), which are far more common and have established clinical utility. CYP3A4*2 is too rare for population-level clinical guidelines, but individual carriers benefit from genotype-aware prescribing.

Interactions

CYP3A4*2 can combine with CYP3A4*22 (rs35599367) or CYP3A5*3 (rs776746) on the other allele, producing compound genotypes with potentially greater reduction in total CYP3A enzyme activity. In a compound heterozygote carrying both CYP3A4*2 and CYP3A4*22 (one on each chromosome), overall CYP3A4 activity would be reduced from both alleles, yielding a predicted poor metabolizer phenotype for nifedipine- class substrates. This combination, while rare, would warrant extra caution with CYP3A4 substrates.

Environmental CYP3A4 inhibitors dramatically amplify the effect: grapefruit juice, clarithromycin, ketoconazole, and ritonavir can inhibit CYP3A4 by 3- to 8-fold. For a CYP3A4*2 carrier who already has baseline reduced clearance, adding a strong inhibitor compounds the exposure increase and significantly raises toxicity risk with narrow-therapeutic-index drugs.