Is OTC p.Phe14fs (c.42del) pathogenic?

OTC p.Phe14fs (c.42del) is classified Pathogenic in OTC (ClinVar, No assertion criteria, 1 submitter). No gnomAD frequency available for this variant.

How common is OTC p.Phe14fs (c.42del) in the general population?

OTC p.Phe14fs (c.42del) is no gnomAD frequency available for this variant (gnomAD).

OTC p.Phe14fs

c.42del · rs72552298 · VCV97194

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

ClinGen expert panel — Urea Cycle Disorders VCEP

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

PVS1 PP4_Moderate PM2_Supporting

Curation rationale (ClinGen, verbatim)

The NM_000531.6:c.42del (p.Phe14LeufsTer24) variant in OTC is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 1/10 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; GeneReviews). At least one heterozygous female individual with this variant displayed elevated ammonia, low/normal citrulline and elevated urine orotic acid, which is highly specific for Ornitine Transcarbamilase (PP4_Moderate, PMID:14976564). This variant is absent from gnomAD v41.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as 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): PVS1, PP4_Moderate, PM2_Supporting

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 1 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.57	GERP 0.41, phastCons 0.41

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: OTC
Protein: p.Phe14fs
Coding: c.42del
MANE Select: NM_000531
dbSNP: rs72552298
Type: Deletion
Location: chrX:38352735 (GRCh38)
Structure: AlphaFold pLDDT 91.94 · 4 PDB

Full OTC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

OTC c.299-8del Benign/Likely benign ★★ same type
OTC c.216+1del Pathogenic ★ same type
OTC c.718-2_731del Pathogenic ★ same type
OTC p.Ala218fs Pathogenic ★ same type
OTC p.Asn10fs Pathogenic ★ same type
OTC p.Asn47fs Pathogenic ★ same type
OTC p.Gln270fs Pathogenic ★ same type
OTC p.Gln282fs Likely pathogenic ★ same type

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-phe14fs (accessed [today's date]).

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