Is OTC p.Leu342Pro (c.1025T>C) pathogenic?

OTC p.Leu342Pro (c.1025T>C) is classified Uncertain significance in OTC (ClinVar, Single submitter, 1 submitter; last evaluated 2019-06-16). AlphaMissense: likely pathogenic (0.9746); Absent from gnomAD v4.1; Associated with ornithine carbamoyltransferase deficiency.

What condition is associated with OTC p.Leu342Pro (c.1025T>C)?

OTC p.Leu342Pro (c.1025T>C) is associated with ornithine carbamoyltransferase deficiency (ClinVar).

How common is OTC p.Leu342Pro (c.1025T>C) in the general population?

OTC p.Leu342Pro (c.1025T>C) is absent from gnomAD v4.1 (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.Leu342Pro (c.1025T>C)?

AlphaMissense predicts likely pathogenic (score 0.9746) — an in-silico prediction, not a clinical call.

OTC p.Leu342Pro

c.1025T>C · rs2068592679 · VCV943237

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9746 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ornithine carbamoyltransferase deficiency

ClinGen expert panel — Urea Cycle Disorders VCEP

Likely Pathogenic for ornithine carbamoyltransferase deficiency. Applied ACMG criteria (verbatim):

PP3_Strong PM2_Supporting PS3_Moderate

Curation rationale (ClinGen, verbatim)

The NM_000531.6:c.1025T>C variant in OTC is a missense variant predicted to cause substitution of leucine by proline at amino acid 342 (p.Leu342Pro). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a SCORE of 0.958, which is above the threshold of ≥ 0.932 to apply PP3_Strong, evidence that correlates with impact to OTC function (PP3_Strong). Quantitative growth assay in yeast strains showed <5% wild-type growth activity, indicating that this variant impacts protein function (PMID: 37146589) (PS3_Moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic for X-linked ornithine carbamoyltransferase deficiency. ACMG/AMP criteria met, as specified by the ClinGen Urea Cycle Disorders VCEP (OTC specifications version 1.0.0): PM2_Supporting, PP3_Strong, PS3_Moderate.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9746	likely pathogenic
REVEL	0.958	strongly pathogenic-leaning
SaProt	LLR -15.44	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 68 kb · p 3.9e-05 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: OTC
Protein: p.Leu342Pro
Coding: c.1025T>C
MANE Select: NM_000531
dbSNP: rs2068592679
Type: single nucleotide variant
Location: chrX:38421042 (GRCh38)
Structure: AlphaFold pLDDT 91.94 · 4 PDB
Residue 342: 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.Leu342Met Uncertain significance ★★ ⚠ same residue
OTC p.Leu342fs Pathogenic ★ 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

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-leu342pro (accessed [today's date]).

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