ITPA P32T - GET-Evidence



(ITPA Pro32Thr)

Short summary

This variant is associated with inosine triphosphate pyrophosphohydrolase deficiency and may be associated with an adverse reaction to thiopurine drugs (which are used as immunosuppressants). Homozygotes have no detectable ITPase activity, individuals compound heterozygous with another less severe mutation also have severely reduced enzyme activity.

Variant evidence
Computational 2

NBLOSUM=3, gene associated with phenotype, impair secondary structure, but Polyphen 2 predicts benign effect.

See 12384777.

Functional 2

enzyme extract and yeast expression

See 19631656.

Case/Control 5

significance = 2.5 * 10^-10

See 12384777.

Clinical importance
Severity 3

There are conflicting reports of adverse drug reactions for ITPA deficiency

Treatability 2

Clinical treatment in development.

See unpublished research (below).

Penetrance 1

Most individuals don’t need to take azathiopurine for immunosuppression



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

Heterozygotes for this variant showed a mean ITPase activity of 22.5% while homozygotes showed complete inactivation.

Allele frequency

  • A @ chr20:3193842: 6.1% (656/10758) in EVS
  • A @ chr20:3141841: 5.5% (7/128) in GET-Evidence
  • Frequency shown in summary reports: 6.1% (656/10758)


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PubMed PMID: 12384777

In a study of eight families (one Chinese and the rest Caucasian?) with inosine triphosphate pyrophosphohydrolase deficiency, this variant was found in 5 out of 8 families with ITPase deficiency. The variant is expected to increase alpha-helical structure and impair dimerization of the protein. This variant is predicted increase toxicity of thiopurine drugs.

In some families multiple members were examined, and the proband (first affected member seeking medical attention) is not mentioned. To make a fair comparison with controls, we can reduce this set to single individuals by choosing the individual from each family with the most extreme ITPase deficiency (lowest ITPase activity). Doing this we get 5 homozygous for this allele, 2 heterozygous, 1 non-carrier. (Both heterozygous individuals with compound heterozygous another allele implicated, and the wild-type was homozygous for that allele.) Among 100 controls they found 10 heterozygous for this variant alone and 2 compound heterozygous for this variant and the other implicated variant.

Counting alleles, this is case+: 12, case-: 4, control+: 12, control-: 188. This is extremely significant with p=2.5 * 10^-10. All homozygous individuals have zero ITPase activity and so we can consider this as fully penetrant under a recessive hypothesis.

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PubMed PMID: 15322947

“Azathioprine (AZA), the pro-drug of mercaptopurine, is commonly used in organ transplant patients and for the treatment of chronic inflammatory disease, dermatologic disorders, and rheumatic diseases.”

Prior to AZA therapy, authors recommend prescreening patients for TPMT variants and ITPA P32T to further improve the chances of identifying at-risk patients.

Bierau J, Lindhout M, Bakker JA. Pharmacogenetic significance of inosine triphosphatase. Pharmacogenomics. 2007 Sep;8(9):1221-8. Review. PubMed PMID: 17924837.

The authors conclude: “The pharmacogenetic significance of inosine triphosphatase is a highly debated subject and data published are contradictory; The ITPA 94>A genotype may be associated with azathioprine-induced adverse drug reaction; Carriers of ITPA allelic variants are easily detected by measurement of ITPase activity.”

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PubMed PMID: 19631656

In a series of in-vitro experiments this paper proposes the method of enzyme inactivation by this variant.

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PubMed PMID: 19682085


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PubMed PMID: 20173735

“Finally, because ITPA deficiency seems to be a benign condition, it may be possible to protect against RBV-induced anaemia by pharmacological intervention against ITPA. The identification of inosine triphosphatase deficiency as a major projective factor against RBV-induced haemolytic anaemia therefore not only provides a valuable pharmacogenetic diagnostic, but also a window into red blood cell biology and the processes governing lysis.”



hu604D39 - CGI sample GS00253-DNA_B02_200_37
het A @ chr20:3193842


huBEDA0B - CGI sample GS00253-DNA_C01_200_37
het A @ chr20:3193842




GS06985 - var-GS06985-1100-36-ASM
het A @ chr20:3141842


GS12004 - var-GS12004-1100-36-ASM
het A @ chr20:3141842


GS18508 - var-GS18508-1100-36-ASM
het A @ chr20:3141842


GS19017 - var-GS19017-1100-36-ASM
het A @ chr20:3141842


GS19025 - var-GS19025-1100-36-ASM
het A @ chr20:3141842


Other external references

  • rs1127354
  • Score: 0.006 (benign)

Other in silico analyses

  • NBLOSUM100 score = 4
  • GET-Evidence autoscore = 2

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Gene search

"GENE" or "GENE A123C":

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