Is OTC p.Pro75Thr (c.223C>A) pathogenic?

OTC p.Pro75Thr (c.223C>A) is classified Uncertain significance in OTC (ClinVar, Single submitter, 2 submitters; last evaluated 2023-12-20). AlphaMissense: likely benign (0.2653); Very rare (popmax 8.66e-05%); Associated with ornithine carbamoyltransferase deficiency.

What condition is associated with OTC p.Pro75Thr (c.223C>A)?

OTC p.Pro75Thr (c.223C>A) is associated with ornithine carbamoyltransferase deficiency (ClinVar).

How common is OTC p.Pro75Thr (c.223C>A) in the general population?

OTC p.Pro75Thr (c.223C>A) is very rare (popmax 8.66e-05%) (gnomAD).

How is Ornithine transcarbamylase deficiency inherited?

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

What do computational predictors say about OTC p.Pro75Thr (c.223C>A)?

AlphaMissense predicts likely benign (score 0.2653) — an in-silico prediction, not a clinical call.

OTC p.Pro75Thr

c.223C>A · VCV3343914

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2653 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.66e-05%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

ornithine carbamoyltransferase deficiency

Computational evidence

Protein change
AlphaMissense	0.2653	likely benign
REVEL	0.61	indeterminate
SaProt	LLR -10.20	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 68 kb · p 3.9e-05 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.66e-05%

Overall 8.66e-05% 1/1,155,303 alleles · very rare exomes 1/1,042,606 · genomes 0/112,697 · 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.Pro75Thr
Coding: c.223C>A
MANE Select: NM_000531
Type: single nucleotide variant
Location: chrX:38369802 (GRCh38)
Structure: AlphaFold pLDDT 91.94 · 4 PDB

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 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
OTC c.663+2T>C 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-pro75thr (accessed [today's date]).

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