rs67784355 — CYP3A4 *11 (Thr363Met)

Rare missense variant in CYP3A4 that reduces protein expression and enzymatic activity across multiple drug substrates

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CYP3A4*11 — A Rare Variant with Real Consequences for Drug Clearance

CYP3A4 is the dominant drug-metabolizing enzyme in the human liver and intestine, processing approximately half of all prescription medications11 approximately half of all prescription medications
Including statins, immunosuppressants, benzodiazepines, calcium channel blockers, HIV antiretrovirals, antifungals, and many anticancer agents. The CYP3A4*11 allele, defined by rs67784355 (c.1088C>T on the coding strand; p.Thr363Met), is one of the rarest functionally characterized CYP3A4 variants — but when it occurs, it produces a measurably compromised enzyme.

Threonine at position 363 sits within the substrate recognition site 5 (SRS-5)22 substrate recognition site 5 (SRS-5)
One of six substrate-recognition sites lining the CYP3A4 active site; SRS-5 contributes to the hydrogen-bonding network that stabilizes the active site architecture and positions substrates for catalysis. Replacing this threonine with a bulkier methionine disturbs the local protein structure, reducing both how much enzyme is produced and how stable it is once made.

The Mechanism

CYP3A4 is encoded on the minus (antisense) strand of chromosome 7. The *11 allele introduces a C→T change at position 1088 of the coding sequence (NM_017460.6:c.1088C>T), which on the genomic plus strand corresponds to a G→A substitution at rs67784355. The encoded threonine (polar, hydroxyl side chain) at codon 363 is replaced by methionine (hydrophobic, larger side chain). This is not a conservative substitution — methionine cannot fulfill the hydrogen-bonding role of threonine in the SRS-5 network.

In vitro expression studies33 In vitro expression studies
Using baculovirus-insect cell and mammalian expression systems to produce recombinant CYP3A4 protein consistently find that CYP3A4*11 produces substantially less functional apoprotein than wild-type CYP3A4*1. The carbon monoxide-difference spectra44 carbon monoxide-difference spectra
A spectrophotometric test of functional CYP content that measures correctly folded heme-containing protein of *11-expressing cells show reduced signal — meaning fewer active enzyme molecules, not just impaired ones.

The Evidence

Four independent in vitro studies characterize CYP3A4*11 across different substrates:

Loperamide: Wang et al. (2019)55 Wang et al. (2019)
Functional characteristics of CYP3A4 allelic variants on the metabolism of loperamide in vitro found that CYP3A4*11's intrinsic clearance (CLint) for N-demethylation of loperamide was approximately 5.7-fold lower than wild-type, placing it among the most functionally impaired alleles tested. The authors attributed the deficit to protein instability from the bulky methionine substitution disrupting the tertiary structure at position 363.

Quinine: Gao et al. (2019)66 Gao et al. (2019)
Enzymatic activities of CYP3A4 allelic variants on quinine 3-hydroxylation in vitro showed that CYP3A4*11 expressed at particularly low apoprotein levels compared to wild-type, consistent with reduced protein stability, and displayed reduced quinine hydroxylation activity. Five variants in total showed this pattern of low expression — *11 was among the most severely affected.

Midazolam and testosterone: Kato et al. (2021)77 Kato et al. (2021)
Functional characterization of 40 CYP3A4 variants by assessing midazolam 1'-hydroxylation and testosterone 6β-hydroxylation confirmed reduced T363M expression in mammalian cells, noting that this substitution affects either protein expression or stability. The kinetic analysis placed *11 among the variants with meaningfully reduced catalytic efficiency.

Original identification: Sata et al. (2000)88 Sata et al. (2000)
CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12 first identified *11 from human liver samples and demonstrated its altered catalytic activity, establishing residue 363 as functionally important.

The limitation of all current evidence is that it is exclusively in vitro. The 2023 joint consensus genotyping recommendation99 2023 joint consensus genotyping recommendation
From AMP, CPIC, CAP, DPWG, ESPT, and PharmGKB explicitly excluded CYP3A4*11 from its Tier 1 and Tier 2 clinical assay recommendations because of this limitation — no pharmacokinetic studies in human carriers have been published. The variant is too rare to recruit sufficient carriers for in vivo trials under normal circumstances.

Practical Implications

Because clinical pharmacokinetic data are absent, prescribers cannot rely on published dosing guidelines for *11 carriers as they can for CYP3A4*22 or CYP3A5*1/*3. However, the consistent direction of the in vitro evidence — reduced enzyme levels, reduced clearance across multiple chemically distinct substrates — makes it reasonable to apply the same precautions used for other CYP3A4 reduced-function alleles.

The drugs of greatest concern are those with narrow therapeutic windows metabolized primarily by CYP3A4: tacrolimus and cyclosporine (transplant immunosuppressants), statins particularly atorvastatin and simvastatin, midazolam and other benzodiazepines, and cardiotoxic drugs like loperamide (at high doses). For each of these, standard doses may produce higher-than-expected plasma concentrations in *11 carriers.

Importantly, CYP3A4 inhibitors (grapefruit, clarithromycin, ketoconazole, ritonavir) compound an already-reduced enzyme capacity — the additive effect of genetic reduction plus pharmacological inhibition can push drug levels into the toxic range.

Interactions

CYP3A4*11 exists in the same genetic neighborhood as the more common and better-studied CYP3A4 variants. The CYP3A4*22 allele (rs35599367)1010 CYP3A4*22 allele (rs35599367)
An intronic splice variant causing ~50% reduced CYP3A4 mRNA, with established clinical guidelines for tacrolimus dosing is the most clinically relevant partner. CYP3A4*38 was defined precisely because rs67784355 was found in cis with the CYP3A4*3-defining variant in some haplotypes, meaning the same chromosome can carry multiple reduced-function alleles simultaneously.

CYP3A5 status (rs776746) is critical context for CYP3A4*11 carriers. CYP3A5 is a closely related enzyme that partially compensates for reduced CYP3A4 activity. If a *11 carrier is also a CYP3A5 non-expresser (*3/*3, the case for ~85% of Europeans), total CYP3A enzyme capacity is substantially diminished. A CYP3A5 expresser who carries *11 may show near-normal overall CYP3A clearance because CYP3A5 compensates — the opposite is true in non-expressers.

Gene-drug interactions are equally important. Strong CYP3A4 inhibitors added to an already-impaired metabolizer create additive metabolic suppression. Any patient carrying CYP3A4*11 who starts an azole antifungal, macrolide antibiotic, or ritonavir-boosted HIV regimen while on a narrow-therapeutic-index CYP3A4 substrate should be monitored intensively.

Drug Interactions

tacrolimus increased_toxicity literature
midazolam dose_adjustment literature
atorvastatin dose_adjustment literature
simvastatin dose_adjustment literature
loperamide increased_toxicity literature
quinine altered_metabolism literature

Genotype Interpretations

What each possible genotype means for this variant.

GG Normal Metabolizer Normal

Standard CYP3A4 enzyme activity — normal clearance of CYP3A4-metabolized drugs

You carry two copies of the normal CYP3A4 sequence at this position. Your CYP3A4*11 status does not impair drug metabolism. This is by far the most common genotype globally — essentially all individuals in all populations carry GG at rs67784355, with the A allele present in fewer than 0.1-0.5% of individuals in any studied population. CYP3A4*11 carriers are rare enough that most prescribers have never knowingly treated one.

AG Intermediate Metabolizer Intermediate

One copy of CYP3A4*11 — moderately reduced enzyme expression and clearance for CYP3A4 substrates

Threonine 363 sits within substrate recognition site 5 (SRS-5) of CYP3A4, where it contributes to the hydrogen-bonding network that maintains the active-site architecture and positions substrates for oxidation. The methionine substitution introduced by the A allele is bulkier and lacks the polar hydroxyl group needed for this network, disrupting protein folding in this region.

Multiple independent in vitro studies using different substrates (loperamide, quinine, midazolam, testosterone) consistently find reduced CYP3A4*11 expression and function. The intrinsic clearance for loperamide was ~5.7-fold lower than wild-type. Quinine studies found particularly low apoprotein expression. These are not marginal findings — the enzyme deficit is large in every assay system tested.

Because you have one normal copy (*1) alongside *11, your total enzyme activity is intermediate — your functional CYP3A4 is diluted but not absent. The normal allele continues to produce functional enzyme, providing partial coverage. Your overall CYP3A4 activity depends heavily on whether you also express CYP3A5: if you are a CYP3A5 expresser (carrying at least one *1 allele of rs776746), your total CYP3A activity may be near-normal; if you are a CYP3A5 non-expresser (*3/*3), your total CYP3A clearance is more substantially reduced.

AA Poor Metabolizer Poor

Two copies of CYP3A4*11 — severely reduced CYP3A4 enzyme expression, very rare genotype

Homozygous CYP3A4*11 has not been observed in published clinical pharmacokinetic studies — the allele is too rare for homozygotes to appear in standard cohorts. All functional predictions are extrapolated from in vitro characterization of heterozygous allele function. In those studies, the *11 allele consistently shows among the most severe reductions: ~5.7-fold lower intrinsic clearance for loperamide, low apoprotein expression by carbon monoxide spectra, reduced quinine hydroxylation. In a homozygous state, both copies of the enzyme are impaired; the only partial compensation comes from CYP3A5 expression (if present) and residual low-level CYP3A4 activity from the small fraction of correctly folded protein.

The practical consequence for a homozygous *11 carrier — if confirmed — would be functional equivalence to a CYP3A4 ultra-poor metabolizer. This would place them in the same category as the rare CYP3A4*20 homozygotes (a Spanish founder allele with frameshift and no enzyme) for purposes of dose adjustment. Standard doses of tacrolimus, cyclosporine, statins, midazolam, fentanyl, and other CYP3A4-dominant substrates would be expected to produce substantially elevated blood levels.

This genotype result warrants clinical genetics referral for confirmation by Sanger or WGS, followed by comprehensive medication review by a clinical pharmacologist or pharmacogenomics specialist.