Is OTC p.Ile194= (c.582C>A) pathogenic?

OTC p.Ile194= (c.582C>A) is classified Benign/Likely benign in OTC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-16). Very rare (popmax 0.00168%, nfe); Associated with ornithine carbamoyltransferase deficiency.

What condition is associated with OTC p.Ile194= (c.582C>A)?

OTC p.Ile194= (c.582C>A) is associated with ornithine carbamoyltransferase deficiency (ClinVar).

How common is OTC p.Ile194= (c.582C>A) in the general population?

OTC p.Ile194= (c.582C>A) is very rare (popmax 0.00168%, nfe) (gnomAD).

How is Ornithine transcarbamylase deficiency inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

OTC p.Ile194=

c.582C>A · rs200564773 · VCV1169772

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00168%, nfe)

Conditions

ornithine carbamoyltransferase 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 -1	GERP -4.4
Overall
CADD	6.405	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00168% European (non-Finnish) · 15/891,191 alleles

Filtering AF 0.00101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000801%

Overall 0.00124% 15/1,205,719 alleles · very rare exomes 11/1,093,660 · genomes 4/112,059 · 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: OTC
Protein: p.Ile194=
Coding: c.582C>A
MANE Select: NM_000531
dbSNP: rs200564773
Type: single nucleotide variant
Location: chrX:38403659 (GRCh38)
Structure: AlphaFold pLDDT 91.94 · 4 PDB
Residue 194: a β-strand

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

Disease context

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

For Ornithine transcarbamylase deficiency (Orphanet):

Inheritance: X-linked recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

OTC p.Ile194Val Conflicting classifications of pathogenicity ★ ⚠ same residue
OTC c.298+2T>G Pathogenic ★★ same condition
OTC c.299-1G>A Likely pathogenic ★★ same condition
OTC c.386+1G>A Pathogenic ★★ same condition
OTC c.540+1G>A Pathogenic ★★ same condition
OTC c.540+1G>T Pathogenic ★★ same condition
OTC c.540+265G>A Pathogenic ★★ same condition
OTC c.663+1G>T 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/otc-p-ile194 (accessed [today's date]).

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