rs2231137 — ABCG2 ABCG2 V12M (Val12Met)

Missense variant in the ABCG2 transporter that impairs membrane localization and alters efflux of drugs, porphyrins, and urate, with the T allele associated with altered antiretroviral drug handling and reduced transporter activity in some cell models

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ABCG2 V12M — When a Transporter Loses Its Place at the Membrane

ABCG2 — also called Breast Cancer Resistance Protein (BCRP) — is one of the most versatile efflux pumps in the body. It sits at the apical surface of intestinal cells, renal tubules, and the blood–brain barrier, where it exports a wide range of substances including uric acid11 uric acid
a metabolic waste product of purine breakdown, porphyrins, anticancer drugs, antibiotics, and antiretroviral medications. The rs2231137 variant encodes a valine-to-methionine substitution at position 12 of the protein — a residue in the first transmembrane segment that influences how ABCG2 folds and reaches the cell membrane.

The Mechanism

The V12M change (T allele on the plus strand; the protein letter change is coded on the minus strand as G>A at nucleotide 34 of the coding sequence) sits at the very beginning of the ABCG2 protein's first predicted transmembrane helix. One cell model study found 22 Kamo et al., Intl J Cancer, 2004 that V12M disrupts apical plasma membrane localization — the protein is synthesized normally but fails to traffic to the correct compartment. Cells expressing V12M showed drug efflux less than one-tenth that of wild-type. However, a second study using membrane vesicles from HEK293 cells 33 Kondo et al., Pharm Res, 2004 found transport activity for estrone sulfate, DHEAS, and methotrexate was comparable to wild-type. The discrepancy likely reflects cell-type and assay differences, making V12M's intrinsic functional impact harder to pin down than the better-characterised Q141K variant (rs2231142), which consistently reduces urate transport by ~53%.

The Evidence

Population genetics paints an interesting picture. The T allele (Met12) occurs at about 4% in Europeans but reaches 27% in East Asians and 23% in Latino/Admixed American populations — a striking frequency difference suggesting different selective pressures across ancestries.

A meta-analysis of 52 studies44 meta-analysis of 52 studies
Shi et al., BMC Med Genet, 2020 found that carrying one or two T alleles at rs2231137 was associated with 36–57% lower odds of gout compared to CC homozygotes. This protective direction for gout is somewhat counterintuitive if V12M reduces urate transport, and may reflect incomplete LD with nearby protective haplotypes, population stratification, or context-dependent functional effects.

In drug-handling contexts, the picture is different. A study of 149 HIV-infected patients 55 Rodrigues et al., Mol Genet Genomic Med, 2024 found that the T allele and the heterozygous CT genotype were associated with increased risk of antiretroviral-induced hepatotoxicity (OR 1.50 for the allele; haplotype OR up to 2.49 in combination with rs2231142). In a small study of 93 Iranian children, 66 Barakat et al., Seizure, 2022 each T allele was associated with approximately 2.4-fold higher odds of drug-resistant epilepsy, suggesting altered antiepileptic drug transport.

An epistatic interaction study in 4,914 Chinese participants 77 Tang et al., Hereditas, 2020 found that rs2231137 interacts with the PKD2 variant rs2728121 to influence urate levels and gout risk, with stronger effects in males (Pint = 0.004).

Practical Actions

The main clinical implications of this variant are in the context of specific drugs whose clearance depends on ABCG2 — particularly antiretrovirals used in HIV treatment and certain antiepileptic drugs. Carriers of the T allele, especially those also carrying risk alleles at the companion ABCG2 variant rs2231142 (Q141K), may have a compounded reduction in ABCG2 transport capacity that warrants monitoring of drug levels and liver enzymes when starting hepatically-cleared medications.

Interactions

The most clinically important interaction is with rs2231142 (Q141K), the dominant functional variant in ABCG2. Q141K alone reduces urate transport by ~53% and drives most of the ABCG2-gout association. Carrying T alleles at both rs2231137 (V12M) and rs2231142 (Q141K) may compound transporter impairment beyond either variant alone — a haplotype combination studied for drug resistance in cancer cells (PMID 40806557). The 12M/141K haplotype showed 10.7-fold resistance to the anticancer drug mitoxantrone, substantially higher than either variant alone.

There is also a documented epistatic interaction with rs2728121 in the PKD2 gene, which co-regulates urate levels and gout susceptibility through separate renal mechanisms.

Genotype Interpretations

What each possible genotype means for this variant.

CC Standard Transporter Normal

Standard ABCG2 V12M function — Valine at position 12

You carry two C alleles (CC) at rs2231137, which means your ABCG2 protein has the common valine amino acid at position 12. This is the reference configuration for ABCG2 membrane trafficking at this position. About 84% of the global population shares this genotype, though frequencies vary widely — it is the predominant genotype in Europeans (~92% CC) but less common in East Asians (~53% CC) and Latino populations (~61% CC). Your ABCG2 transport function at this locus is not affected by this variant; other ABCG2 variants (notably rs2231142 Q141K) are the primary determinants of overall transporter capacity.

CT Heterozygous V12M Intermediate

One copy of V12M — partially altered ABCG2 membrane trafficking possible

The V12M substitution sits in the first transmembrane segment of ABCG2, near the protein's N-terminus. One study found disturbed apical membrane localization in CT and TT cells, while another found normal transport activity for several substrates. The functional picture is thus mixed at the individual-variant level. What is more clearly established is the haplotype context: when V12M co-occurs with the Q141K variant (rs2231142), ABCG2 transport capacity may be substantially lower than with Q141K alone. The CT genotype at rs2231137 may also modify how certain HIV antiretroviral drugs are cleared, potentially increasing hepatotoxicity risk.

TT Homozygous V12M Reduced

Two copies of V12M — greater ABCG2 membrane trafficking alteration; drug handling may be affected

TT homozygotes carry the full V12M substitution on both ABCG2 alleles. In the most mechanistically oriented study (PMID 14750175), V12M showed disturbed apical plasma membrane localization by confocal microscopy, and drug efflux was less than 1/10 of wild-type cells — a profound reduction if replicated. However, a parallel characterization in HEK293 membrane vesicles (PMID 15553238) found transport of estrone sulfate, DHEAS, and methotrexate was comparable to wild-type V12 protein. The discrepancy is unresolved; cell type, trafficking context, and assay conditions all influence the result.

What is better established is that the T allele modifies drug response in clinical populations: antiretroviral hepatotoxicity risk (OR ~1.50 per T allele; haplotype OR up to 2.49) and drug-resistant epilepsy odds (~2.4-fold per T allele). In combination with Q141K (rs2231142), the haplotype dramatically increases resistance to mitoxantrone and irinotecan metabolites in cancer cell models. TT homozygotes at rs2231137 should treat their ABCG2 transport status as potentially substantially reduced and prioritize drug-level and liver monitoring with ABCG2-substrate medications.