Is ITPA p.Arg178= (c.534C>A) pathogenic?

ITPA p.Arg178= (c.534C>A) is classified Likely benign in ITPA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-01-14). Very rare (popmax 0.000254%, nfe); Associated with inosine triphosphatase deficiency.

What condition is associated with ITPA p.Arg178= (c.534C>A)?

ITPA p.Arg178= (c.534C>A) is associated with inosine triphosphatase deficiency (ClinVar).

How common is ITPA p.Arg178= (c.534C>A) in the general population?

ITPA p.Arg178= (c.534C>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

ITPA p.Arg178=

c.534C>A · rs1600541852 · VCV1561210

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

inosine triphosphatase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.071	GERP -3.3, phastCons 0.56
Overall
CADD	6.725	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,008 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,948 alleles · very rare exomes 3/1,461,608 · genomes 0/152,340 · joint denominator

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.Arg178=
Coding: c.534C>A
MANE Select: NM_033453
dbSNP: rs1600541852
Type: single nucleotide variant
Location: chr20:3223411 (GRCh38)
Gene constraint: LOEUF 1.159 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.37 · 4 PDB
Residue 178: a UniProt-annotated variant site (in dee35; uncertain significance); an α-helix; a binding site

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 p.Arg178Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
ITPA p.Arg178His Uncertain significance ★ ⚠ same residue
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

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-arg178 (accessed [today's date]).

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