rs2242480 — CYP3A4 *1G

CYP3A4*1G — The Intronic Variant That Quietly Reshapes Drug Dosing

CYP3A4 is the most versatile drug-metabolizing enzyme in the human body, responsible for processing approximately 50% of all prescription medications — from transplant immunosuppressants and statins to psychiatric drugs and opioids. The *1G variant (rs2242480) sits in intron 10 of CYP3A4, a seemingly innocuous location. Yet its effects on enzyme expression are clinically meaningful enough to appear on transplant pharmacogenomics panels and to influence tacrolimus and sirolimus trough concentrations by two- to three-fold in transplant patients.

Unlike the well-characterized *22 splice variant (rs35599367), *1G does not disrupt a splicing factor binding site. Instead, its mechanism runs through an indirect regulatory pathway involving a long noncoding RNA.

The Mechanism

Collins and Wang (2022)¹¹ Collins and Wang (2022)
Regulation of CYP3A4 and CYP3A5 by a lncRNA: a potential underlying mechanism explaining the CYP3A4*1G association identified AC069294.1, an antisense [long noncoding RNA | lncRNA: a class of RNA molecules longer than 200 nucleotides that do not code for protein but regulate gene expression] as a negative regulator of both CYP3A4 and CYP3A5. Knockdown of this lncRNA increased CYP3A4 mRNA approximately 3-fold; overexpression reduced it by 89%. The rs2242480 T allele (*1G) sits approximately 2.7 kb upstream of the lncRNA gene and is associated with 1.26-fold increased lncRNA expression (P<0.0001). Downstream of this, *1G carriers show 31% lower CYP3A4 expression (P=0.008) and 39% lower CYP3A5 expression (P=0.004). Yang et al. (2023)²² Yang et al. (2023)
CYP3A4 and CYP3A5 Expression is Regulated by CYP3A4*1G in CRISPR/Cas9-Edited HepG2 Cells confirmed this in engineered cell lines, showing allele-dependent reduction in both mRNA and protein, with decreased tacrolimus metabolism particularly in heterozygous GA (plus-strand: CT) cells.

On the chromosome, CYP3A4 lies on the minus strand. The variant is described in coding-strand notation as c.1026+12G>A, but in genome files (which always use the plus strand), it reads as a C>T change at chromosome 7 position 99,763,842 (GRCh38). The reference allele C corresponds to the wild-type *1 haplotype; the alternate T allele defines *1G.

The Evidence

The most clinically relevant evidence comes from transplant medicine. Miura et al. (2011)³³ Miura et al. (2011)
Impact of the CYP3A4*1G polymorphism and its combination with CYP3A5 genotypes on tacrolimus pharmacokinetics in renal transplant patients followed 136 renal transplant recipients and found that CYP3A4*1G carriers had significantly lower dose-adjusted tacrolimus AUC and trough concentrations — an effect approximately half the magnitude of CYP3A5 expresser status but independently significant (P=0.018). Dong et al. (2022)⁴⁴ Dong et al. (2022)
CYP3A7, CYP3A4, and CYP3A5 polymorphisms in recipients influence tacrolimus concentrations after liver transplantation found CC recipients had approximately twice the dose-adjusted trough concentration as TC/TT carriers (189.8 vs 99.7 ng/mL per mg/kg/day, P<0.001) in 138 liver transplant patients. Uesugi et al. (2013)⁵⁵ Uesugi et al. (2013)
CYP3A4*1G polymorphism and tacrolimus in liver transplant patients observed similar direction effects in a 410-patient Japanese cohort, with CYP3A4*1/*1 donors yielding 37% higher concentration/dose ratios than *1/*1G donors in the first week post-transplant.

For sirolimus, a 2020 study of 69 renal transplant recipients⁶⁶ a 2020 study of 69 renal transplant recipients
CYP3A4 rs2242480 associated with sirolimus trough concentrations found CC carriers achieved 533 vs 157–143 (ng/mL)/mg/kg trough concentrations compared to TC and TT carriers respectively (P<0.0001) — a greater than three-fold difference that could mean the difference between subtherapeutic and supratherapeutic exposure.

Beyond transplant medicine, a meta-analysis of 18 studies encompassing 2,546 epilepsy patients⁷⁷ a meta-analysis of 18 studies encompassing 2,546 epilepsy patients
Associations between CYP3A4, CYP3A5 and SCN1A polymorphisms and carbamazepine metabolism found the *1G allele (G in coding-strand notation, T in plus-strand) markedly reduced plasma carbamazepine concentrations. For psychiatric drugs, Dai et al. (2026)⁸⁸ Dai et al. (2026)
CYP3A4 rs2242480 and lurasidone in Chinese bipolar depression modeled 133 patients and found CC carriers had 25% lower lurasidone clearance than TT carriers (330 vs 441 L/h), translating to meaningfully higher drug exposure at equivalent doses.

Practical Actions

The primary clinical application of CYP3A4*1G genotyping is in transplant medicine, where tacrolimus and sirolimus have narrow therapeutic windows — the difference between rejection and toxicity. CC homozygotes (the wild-type) metabolize CYP3A4 substrates efficiently and require standard doses. CT heterozygotes (*1/*1G) have moderately reduced enzyme activity; for tacrolimus and sirolimus, starting doses may need upward adjustment or more frequent monitoring to reach target trough levels. TT homozygotes (*1G/*1G) have the greatest reduction in CYP3A4 expression and the lowest drug clearance; they may achieve target tacrolimus/sirolimus levels at lower doses than standard, reducing nephrotoxicity risk.

For CYP3A4-metabolized statins (atorvastatin, simvastatin, lovastatin), TT carriers accumulate higher statin levels and may be at increased risk of myopathy at standard doses. The statin evidence is more limited than for immunosuppressants, but the directionality is consistent.

Interactions

CYP3A4*1G and CYP3A4*22 (rs35599367) are independent variants in the same gene. A patient carrying both the *1G and *22 alleles would be expected to have compounded reductions in CYP3A4 activity. Similarly, CYP3A5 expresser status (rs776746 *1/*3) strongly modifies the *1G effect — Miura et al.⁹⁹ Miura et al.
Tacrolimus PKs in renal transplant showed the lowest dose-adjusted AUC occurred in patients who were both *1G carriers and CYP3A5 expressers, because CYP3A5 expression itself boosts metabolic capacity that the *1G variant then partially suppresses. For a complete picture of CYP3A metabolizer phenotype, both rs2242480 (*1G) and rs776746 (CYP3A5*3) should be considered together.