Is OTC p.Leu148Phe (c.444G>C) pathogenic?

OTC p.Leu148Phe (c.444G>C) is classified Pathogenic in OTC (ClinVar, No assertion criteria, 2 submitters; last evaluated 1997-03-17). AlphaMissense: likely pathogenic (0.9269); Absent from gnomAD v4.1; Associated with ornithine carbamoyltransferase deficiency.

What condition is associated with OTC p.Leu148Phe (c.444G>C)?

OTC p.Leu148Phe (c.444G>C) is associated with ornithine carbamoyltransferase deficiency (ClinVar).

How common is OTC p.Leu148Phe (c.444G>C) in the general population?

OTC p.Leu148Phe (c.444G>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.Leu148Phe (c.444G>C)?

AlphaMissense predicts likely pathogenic (score 0.9269) — an in-silico prediction, not a clinical call.

OTC p.Leu148Phe

c.444G>C · rs66741318 · VCV11011

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9269 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ornithine carbamoyltransferase deficiency

Computational evidence

Protein change
AlphaMissense	0.9269	likely pathogenic ✓ concordant with ClinVar
REVEL	0.898	moderately pathogenic-leaning
SaProt	LLR -12.95	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 68 kb · p 3.9e-05 · regional, not allelic
Overall
CADD	23.7	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

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.Leu148Phe
Coding: c.444G>C
MANE Select: NM_000531
dbSNP: rs66741318
Type: single nucleotide variant
Location: chrX:38401332 (GRCh38)
Structure: AlphaFold pLDDT 91.94 · 4 PDB
Residue 148: an α-helix; a UniProt-annotated variant site (in otcd)

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.Leu148Ser Likely pathogenic ★ same residue
OTC p.Leu148Trp 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-leu148phe (accessed [today's date]).

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