ITPA

Chr 20AR

inosine triphosphatase

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

NCBI Gene: 3704 ENSG00000125877 UniProt: Q9BY32 OMIM: 147520

The encoded protein functions as an inosine triphosphate pyrophosphohydrolase that hydrolyzes inosine triphosphate and deoxyinosine triphosphate to monophosphate nucleotides and diphosphate in the cytoplasm. Mutations cause autosomal recessive inosine triphosphatase deficiency, which leads to ITP accumulation in red blood cells, and developmental and epileptic encephalopathy 35. The pathogenic mechanism appears to involve dominant-negative effects of mutant proteins.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 1.352 OMIM phenotypes

Clinical Summary— ITPA

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Gene-Disease Validity (ClinGen)

genetic developmental and epileptic encephalopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

43 unique Pathogenic / Likely Pathogenic· 127 VUS of 361 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

0.12Z-score

OE missense 0.97 (0.83–1.13)

111 obs / 114.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.84 (0.53–1.35)

0≤0.351.4

Missense OE?0.97 (0.83–1.13)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 12 / 14.4Missense obs/exp: 111 / 114.7Syn Z: -0.45

This gene — mechanism propensity

0.6743th %ile

GOF

0.3689th %ile

LOF

0.3066th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

361 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24

Likely Pathogenic19

VUS127

Likely Benign146

Benign29

Conflicting5

Pathogenic

Likely Pathogenic

127

VUS

146

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	20	0	4	0	24
Likely Pathogenic	17	2	0	0	19
VUS	4	102	20	1	127
Likely Benign	1	33	67	45	146
Benign	0	5	22	2	29
Conflicting	—				5
Total	42	142	113	48	350

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 49) ClinVar copy-number / structural variants overlap ITPA — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →