rs1800462 — TPMT *2

TPMT*2 — The Original Thiopurine Deficiency Allele, Independent of the *3 Cluster

TPMT (thiopurine S-methyltransferase) is the enzyme that inactivates thiopurine drugs¹¹ inactivates thiopurine drugs
Azathioprine, 6-mercaptopurine, and thioguanine — used for inflammatory bowel disease, autoimmune conditions, organ transplantation, and childhood leukemia maintenance by methylating them to inert metabolites. When TPMT activity is reduced or absent, these drugs are diverted into a pathway that generates highly toxic thioguanine nucleotides, which incorporate into DNA and cause life-threatening bone marrow suppression at standard doses. TPMT*2 (rs1800462) was the first TPMT deficiency allele ever identified — described by Krynetski and colleagues in 1995 — and it remains one of the four clinically relevant no-function star alleles tested before thiopurine prescription. Unlike the *3 cluster (*3A, *3B, *3C), which dominates TPMT deficiency in Europeans, *2 is a completely independent functional allele on its own chromosomal background and is the rarer of the two European no-function variant classes.

The Mechanism

TPMT*2 is a single-nucleotide substitution at position 238 of the TPMT coding sequence (c.238G>C) that changes alanine 80 to proline²² alanine 80 to proline
p.Ala80Pro — proline introduces a rigid kink into the protein backbone, disrupting local secondary structure near the SAM-binding pocket in the methyltransferase domain. TPMT is on the minus strand of chromosome 6, so the coding-strand c.238G>C mutation corresponds to a plus-strand C→G substitution at chr6:18143724 (GRCh38). Functional studies by Tai and colleagues³³ Tai and colleagues
Tai HL et al. Enhanced proteasomal degradation of mutant TPMT (TPMT*3A and TPMT*2) in humans. PNAS 1997 showed that the Ala80Pro substitution destabilizes the folded protein, marks it for ubiquitin-dependent degradation⁴⁴ ubiquitin-dependent degradation
The mutant enzyme has a half-life roughly 15-fold shorter than wild-type TPMT, with near-complete turnover via the 26S proteasome, and leaves cells with essentially no functional TPMT from the 2 allele. In vitro, TPMT*2 retains only about 1% of wild-type catalytic activity — roughly a **100-fold reduction* — making it functionally equivalent to the *3A and *3C no-function alleles for clinical purposes.

The Evidence

TPMT is the most thoroughly characterised pharmacogene in clinical practice. The CPIC thiopurine dosing guideline⁵⁵ CPIC thiopurine dosing guideline
Clinical Pharmacogenetics Implementation Consortium — Level A evidence, the highest tier for clinical implementation has been published since 2011 and updated multiple times since. Every CPIC version classifies TPMT*2 as a no-function allele with activity score 0, functionally identical to *3A, *3B, and *3C for dosing purposes. The original 2011 guideline⁶⁶ original 2011 guideline
Relling MV et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2011 named *2, *3A, *3B, and *3C as the four variant alleles that should be tested in routine clinical practice — a panel that remains standard. The 2018 update⁷⁷ 2018 update
Relling MV et al. CPIC Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. Clin Pharmacol Ther 2019 extended the framework to NUDT15 (the dominant thiopurine safety gene in East Asians) and refined the dose-reduction recommendations. The original molecular identification of TPMT*2⁸⁸ molecular identification of TPMT*2
Krynetski EY et al. A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase. Proc Natl Acad Sci USA 1995 came from cloning and sequencing TPMT cDNA from a TPMT-deficient patient who had experienced severe myelosuppression on 6-mercaptopurine. Population studies⁹⁹ Population studies
Otterness DM et al. Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin Pharmacol Ther 1997 place the TPMT*2 allele frequency at roughly 0.2-0.5% in Europeans, making it 5-10 times less common than the *3A haplotype but still responsible for a measurable fraction of TPMT-deficient individuals of European ancestry. TPMT*2 is essentially absent in East Asian and South Asian populations, where NUDT15 variants (rs116855232 in particular) are the dominant cause of thiopurine toxicity. The FDA includes TPMT status in its pharmacogenomic biomarker table¹⁰¹⁰ pharmacogenomic biomarker table for azathioprine, mercaptopurine, and thioguanine, with package inserts explicitly recommending pre-treatment genotyping.

Practical Implications

If you carry one or two copies of TPMT*2, you are at risk for severe thiopurine-induced bone marrow suppression at standard doses — the same clinical risk carried by people with TPMT*3A/3B/*3C variants. European populations carry the *2 variant at roughly 0.2-0.5% allele frequency, meaning about 1 in 200-400 people of European ancestry is heterozygous (one functional TPMT allele from the *2), and homozygous *2/*2 is extremely rare. The CPIC 2025 guideline recommends starting at 30-80% of the standard dose for intermediate metabolizers (one no-function allele of any type) and 10% of the standard dose or an alternative medication for poor metabolizers (two no-function alleles — whether *2/*2, *2/*3A, *2/*3C, or any other combination). Because TPMT deficiency classification depends on **all variant alleles in combination*, anyone found to carry *2 must also be genotyped for *3B (rs1800460), *3C (rs1142345), and NUDT15 (rs116855232) to determine the complete metabolizer phenotype. Missing a second variant on the other chromosome is the classic way that a compound heterozygous poor metabolizer gets labeled as an intermediate metabolizer and receives a dangerous dose.

Interactions

The most clinically important interaction for TPMT*2 is with other TPMT no-function alleles in trans (on the opposite chromosome). TPMT*2 is on a completely different chromosomal background from the 3 cluster — it is NOT part of the *3A haplotype — which means someone carrying *2 plus *3A in trans, or *2 plus *3B alone, or *2 plus *3C alone, is a **compound heterozygous poor metabolizer* with essentially zero TPMT activity and the same dosing requirements as a *3A/*3A homozygote (10% of standard dose or thiopurine avoidance entirely). Clinical labs distinguish *2 carriers by direct genotyping at rs1800462¹¹¹¹ direct genotyping at rs1800462
Most commercial TPMT panels test *2, *3A, *3B, and *3C simultaneously — but some older panels or raw-data imports may miss *2 entirely, which is why this rsid must be part of any TPMT pharmacogenomic pipeline. If your genome file shows rs1800462(G) combined with rs1142345(C) or rs1800460(T), your prescriber should treat you as a poor metabolizer until haplotype phasing confirms otherwise.

A second critical interaction is with NUDT15 (rs116855232), the other thiopurine safety gene. NUDT15 loss-of-function variants act on a downstream step of thiopurine metabolism, and individuals carrying variants in both TPMT and NUDT15 require larger dose reductions than predicted by either gene alone. Both genes should always be checked together before thiopurine prescription. Finally, co-administration of allopurinol¹²¹² allopurinol
Xanthine oxidase inhibitor used for gout; blocks an alternate thiopurine inactivation pathway or febuxostat with thiopurines creates a double-blockade that is particularly dangerous in TPMT variant carriers — the FDA label instructs reducing azathioprine to 25% of the standard dose when combined with allopurinol, and that reduction must be applied on top of any TPMT-based dose reduction.