TPMT Y240C - GET-Evidence



(TPMT Tyr240Cys)

Short summary

Alone, this variant is known as TPMT*3C — but often, especially in Caucasians, it is found together with another nonsynonymous variant (A154T) to produce the TPMT*3A variant. Both variants are associated with loss of thiopurine methyltransferase (TPMT) activity, although *3C is milder than *3A. Inability to metabolize thiopurine drugs can lead to severe adverse reactions. Heterozygotes may be advised to take a reduced dosage due to reduced metabolism of the drug.

Variant evidence
Computational 3

NBLOSUM=4, gene is associated with the disease, Polyphen 2 predicts probably damaging

Functional -
Case/Control 5

Numerous reports.

See Evans WE 2004 (15228163), 15298741, Wang L et al. 2010 (20154640), Ford LT et al. 2010 (20354201).

Clinical importance
Severity 3

Can have adverse reaction to thiopurine overdose.

Treatability 5

Halve dosage for carriers; avoid thiopurines or very low doses for homozygotes.

See 15298741.

Penetrance 2

Homozygotes at severe risk, but most people never need to take thiopurine drugs



Low clinical importance, pharmacogenetic

(The "low clinical importance, " qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary

This variant is also known as TPMT3*C

show discussion


This variant is present in PharmGKB as rs1142345; see

Allele frequency

  • C @ chr6:18130918: 4.6% (496/10740) in EVS
  • C @ chr6:18238896: 6.2% (8/128) in GET-Evidence
  • Frequency shown in summary reports: 4.6% (496/10740)


Evans WE. Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy. Ther Drug Monit. 2004 Apr;26(2):186-91. Review. PubMed PMID: 15228163.

Notes that this variant is also called TPMT*3C. It is ancestral to a double-variant TPMT*3A, which is the combination of both Ala154Thr and Tyr240Cys variants. This allele is one of the major deficiency causing alleles in caucasians and africans. Other variants can also contribute to TPMT deficiency, including TPMT*2 (Ala80Pro) and TPMT*3B (460G>A).

Sanderson J, Ansari A, Marinaki T, Duley J. Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy? Ann Clin Biochem. 2004 Jul;41(Pt 4):294-302. Review. PubMed PMID: 15298741.

Authors report 50% enzyme activity for carriers and none for homozygotes. Report that a 50% dose of thiopurines results in normal response for carriers.

Wang L, Pelleymounter L, Weinshilboum R, Johnson JA, Hebert JM, Altman RB, Klein TE. Very important pharmacogene summary: thiopurine S-methyltransferase. Pharmacogenet Genomics. 2010 Jun;20(6):401-5. PubMed PMID: 20154640.

In a review of the TPMT alleles, this allele is noted as being the most common allele in the African-American and East Asian populations, and the decrease in enzyme levels is not as profound as that caused by *3A or *3B.

Ford LT, Berg JD. Thiopurine S-methyltransferase (TPMT) assessment prior to starting thiopurine drug treatment; a pharmacogenomic test whose time has come. J Clin Pathol. 2010 Apr;63(4):288-95. PubMed PMID: 20354201.

Homozygotes are at severe risk of developing myelosuppression if treated with standard doses of thiopurine drugs, and deaths have occurred. Never-the-less, accounts for only 5–10% of adverse reactions to thiopurine drugs and about 30% cases of neutropenia. Non-genetic factors such as diet, drug interactions, and genetic variation of other enzymes involved in thiopurine drug metabolism have also been implicated.


hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het C @ chr6:18130918


hu0D879F - CGI sample GS00253-DNA_G01_200_37
hom C @ chr6:18130918


huC30901 - CGI sample GS00253-DNA_B01_200_37
het C @ chr6:18130918



GS18505 - var-GS18505-1100-36-ASM
het C @ chr6:18238897


GS19703 - var-GS19703-1100-36-ASM
het C @ chr6:18238897


GS19704 - var-GS19704-1100-36-ASM
het C @ chr6:18238897


GS19735 - var-GS19735-1100-36-ASM
het C @ chr6:18238897


Other external references

  • rs1142345
  • Score: 1.0 (probably damaging)

Other in silico analyses

  • NBLOSUM100 score = 6
  • GET-Evidence autoscore = 4

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Gene search

"GENE" or "GENE A123C":

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