ITPA

Chr 20AR

inosine triphosphatase

Also known as: C20orf37, DEE35, HLC14-06-P, ITPase, My049, NTPase, dJ794I6.3

NCBI Gene: 3704ENSG00000125877UniProt: Q9BY32

This gene encodes an inosine triphosphate pyrophosphohydrolase. The encoded protein hydrolyzes inosine triphosphate and deoxyinosine triphosphate to the monophosphate nucleotide and diphosphate. This protein, which is a member of the HAM1 NTPase protein family, is found in the cytoplasm and acts as a homodimer. Defects in the encoded protein can result in inosine triphosphate pyrophosphorylase deficiency which causes an accumulation of ITP in red blood cells. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

Primary Disease Associations & Inheritance

[Inosine triphosphatase deficiency]MIM #613850
Developmental and epileptic encephalopathy 35MIM #616647
AR
393
ClinVar variants
69
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ITPA
🧬
Gene-Disease Validity (ClinGen)
developmental and epileptic encephalopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
69 Pathogenic / Likely Pathogenic· 144 VUS of 393 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.35LOEUF
pLI 0.000
Z-score 0.58
OE 0.84 (0.53–1.35)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.12Z-score
OE missense 0.97 (0.83–1.13)
111 obs / 114.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.84 (0.53–1.35)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.83–1.13)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.08
0≤1.21.6
LoF obs/exp: 12 / 14.4Missense obs/exp: 111 / 114.7Syn Z: -0.45

ClinVar Variant Classifications

393 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic49
Likely Pathogenic20
VUS144
Likely Benign146
Benign29
Conflicting5
49
Pathogenic
20
Likely Pathogenic
144
VUS
146
Likely Benign
29
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
1
35
1
49
Likely Pathogenic
12
2
6
0
20
VUS
2
102
39
1
144
Likely Benign
0
33
67
46
146
Benign
0
5
22
2
29
Conflicting
—5
Total2614316950393

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ITPA · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

[Inosine triphosphatase deficiency]

MIM #613850

Molecular basis of disorder known

Developmental and epileptic encephalopathy 35

MIM #616647

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures.
Burgess R et al.·Ann Neurol
2019
Neurodegeneration and Early Infantile Epilepsy Associated with ITPA Variants: A Case Series and Review of Literature.
Sharma Y et al.·Neuropediatrics
2022Review
A disease spectrum for ITPA variation: advances in biochemical and clinical research.
Burgis NE·J Biomed Sci
2016Review
An ITPA Enzyme with Improved Substrate Selectivity.
Burgis NE et al.·Protein J
2024
Impact of IL28B, ITPA and PNPLA3 genetic variants on therapeutic outcome and progression of hepatitis C virus infection.
Rembeck K et al.·Pharmacogenomics
2015Review
Effects of ribavirin/sofosbuvir treatment and ITPA phenotype on endogenous purines.
Jimmerson LC et al.·Antiviral Res
2017
The ITPA c.94C>A and g.IVS2+21A>C sequence variants contribute to missplicing of the ITPA gene.
Arenas M et al.·Biochim Biophys Acta
2007
Disease-associated inosine misincorporation into RNA hinders translation.
Schroader JH et al.·Nucleic Acids Res
2022
ITPA-associated developmental and epileptic encephalopathy: characteristic neuroradiological features with novel clinical and biochemical findings.
Garg M et al.·Epileptic Disord
2022
Translating pharmacogenetics into clinical practice: interleukin (IL)28B and inosine triphosphatase (ITPA) polymophisms in hepatitis C virus (HCV) infection.
Cariani E et al.·Clin Chem Lab Med
2011Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools