Is OTC p.Ser340Phe (c.1019C>T) pathogenic?

OTC p.Ser340Phe (c.1019C>T) is classified Pathogenic/Likely pathogenic in OTC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-16). AlphaMissense: ambiguous (0.5463); Absent from gnomAD v4.1; Associated with ornithine carbamoyltransferase deficiency.

What condition is associated with OTC p.Ser340Phe (c.1019C>T)?

OTC p.Ser340Phe (c.1019C>T) is associated with ornithine carbamoyltransferase deficiency (ClinVar).

How common is OTC p.Ser340Phe (c.1019C>T) in the general population?

OTC p.Ser340Phe (c.1019C>T) 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.Ser340Phe (c.1019C>T)?

AlphaMissense predicts ambiguous (score 0.5463) — an in-silico prediction, not a clinical call.

OTC p.Ser340Phe

c.1019C>T · rs1569282905 · VCV618259

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5463 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

ornithine carbamoyltransferase deficiency

Computational evidence

Protein change
AlphaMissense	0.5463	ambiguous
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -9.73	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 68 kb · p 3.9e-05 · regional, not allelic
Overall
CADD	27.3	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.Ser340Phe
Coding: c.1019C>T
MANE Select: NM_000531
dbSNP: rs1569282905
Type: single nucleotide variant
Location: chrX:38421036 (GRCh38)
Structure: AlphaFold pLDDT 91.94 · 4 PDB
Residue 340: 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.Ser340= Likely benign ★ same residue
OTC p.Ser340Pro 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-ser340phe (accessed [today's date]).

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