Is ITPA p.Pro84= (c.252C>T) pathogenic?

ITPA p.Pro84= (c.252C>T) is classified Likely benign in ITPA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-14). Very rare (popmax 0.01%, amr); Associated with inosine triphosphatase deficiency.

What condition is associated with ITPA p.Pro84= (c.252C>T)?

ITPA p.Pro84= (c.252C>T) is associated with inosine triphosphatase deficiency (ClinVar).

How common is ITPA p.Pro84= (c.252C>T) in the general population?

ITPA p.Pro84= (c.252C>T) is very rare (popmax 0.01%, amr) (gnomAD).

ITPA p.Pro84=

c.252C>T · rs751182646 · VCV1146857

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Conditions

inosine triphosphatase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.20	donor loss · deltas
Constraint at this position
Conservation	phyloP -1.4	GERP -4.7, phastCons 0.001
Overall
CADD	6.015	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/60,024 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000805% 13/1,614,188 alleles · very rare exomes 8/1,461,856 · genomes 5/152,332 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,004
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000508%	196,669

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ITPA
Protein: p.Pro84=
Coding: c.252C>T
MANE Select: NM_033453
dbSNP: rs751182646
Type: single nucleotide variant
Location: chr20:3214047 (GRCh38)
Gene constraint: LOEUF 1.159 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.37 · 4 PDB
Residue 84: a β-strand

Full ITPA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

inosine triphosphatase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ITPA c.124+1G>A Pathogenic/Likely pathogenic ★★ same condition
ITPA c.124+2T>C Pathogenic ★★ same condition
ITPA c.264-1G>A Pathogenic/Likely pathogenic ★★ same condition
ITPA p.Gln156Ter Pathogenic/Likely pathogenic ★★ same condition
ITPA p.Trp151Ter Pathogenic ★★ same condition
ITPA p.Trp90Ter Pathogenic/Likely pathogenic ★★ same condition
ITPA c.124+5G>A Uncertain significance ★★ same condition
ITPA c.190-3C>A Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/itpa-p-pro84 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown