Is OTC p.Pro225= (c.675G>A) pathogenic?

OTC p.Pro225= (c.675G>A) is classified Likely benign in OTC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-27). Very rare (popmax 0.00702%, nfe); Associated with ornithine carbamoyltransferase deficiency.

What condition is associated with OTC p.Pro225= (c.675G>A)?

OTC p.Pro225= (c.675G>A) is associated with ornithine carbamoyltransferase deficiency (ClinVar).

How common is OTC p.Pro225= (c.675G>A) in the general population?

OTC p.Pro225= (c.675G>A) is very rare (popmax 0.00702%, 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.Pro225=

c.675G>A · rs376129619 · VCV1143978

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00702%, nfe)

Conditions

ornithine carbamoyltransferase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.28	donor loss · deltas
Constraint at this position
Conservation	phyloP -5.9	GERP -4.4
Overall
CADD	0.044	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00702% European (non-Finnish) · 62/883,409 alleles

Filtering AF 0.00559% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00507%

Overall 0.00543% 65/1,196,925 alleles · very rare exomes 56/1,085,087 · genomes 9/111,838 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00702%	14,249
Remaining individualsnot grpmax-eligible	0.00424%	23,593
South Asian	0.00177%	56,468

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.Pro225=
Coding: c.675G>A
MANE Select: NM_000531
dbSNP: rs376129619
Type: single nucleotide variant
Location: chrX:38408753 (GRCh38)
Structure: AlphaFold pLDDT 91.94 · 4 PDB
Residue 225: a UniProt-annotated variant site (in otcd); a UniProt-annotated variant site (in otcd; neonatal); a UniProt-annotated variant site (in otcd; late onset); an α-helix

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.Pro225Leu Pathogenic ★★ same residue
OTC p.Pro225Ser Likely pathogenic ★★ same residue
OTC p.Pro225Gln Likely pathogenic ★ same residue
OTC p.Pro225Ala Uncertain significance ★ ⚠ same residue
OTC p.Pro225Thr Likely pathogenic ★ same residue
OTC p.Pro225Arg Pathogenic same residue
OTC c.298+2T>G Pathogenic ★★ same condition
OTC c.299-1G>A 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/otc-p-pro225 (accessed [today's date]).

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