rs2231137 — ABCG2 ABCG2 V12M (Val12Met)

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.