Is OTC p.Leu166Phe (c.498G>T) pathogenic?

OTC p.Leu166Phe (c.498G>T) is classified Conflicting classifications of pathogenicity in OTC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-13). AlphaMissense: likely benign (0.204); Ultra-rare (popmax 0.0109%, amr); Associated with ornithine carbamoyltransferase deficiency.

What condition is associated with OTC p.Leu166Phe (c.498G>T)?

OTC p.Leu166Phe (c.498G>T) is associated with ornithine carbamoyltransferase deficiency (ClinVar).

How common is OTC p.Leu166Phe (c.498G>T) in the general population?

OTC p.Leu166Phe (c.498G>T) is ultra-rare (popmax 0.0109%, amr) (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.Leu166Phe (c.498G>T)?

AlphaMissense predicts likely benign (score 0.204) — an in-silico prediction, not a clinical call.

OTC p.Leu166Phe

c.498G>T · rs759911602 · VCV1167469

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.204 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

ornithine carbamoyltransferase deficiency

ClinGen expert panel — Urea Cycle Disorders VCEP

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

BS3_Supporting BA1

Curation rationale (ClinGen, verbatim)

The NM_000531.6:c.498G>T variant in OTC is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 166 (p.Leu166Phe). To our knowledge, this variant has not been reported in the literature in any individuals with OTC deficiency. The Grpmax Filtering allele frequency in gnomAD v4.1.0 is 0.0001094 (5/45704 alleles) in the Admixed American population, with 21 hemizygotes/homozygotes across all populations which is higher than the ClinGen UCD VCEP threshold (>10 hemizygotes/homozygotes) for BA1, and therefore meets this criterion (BA1). Expression of the variant in yeast resulted in 71.5% which is between 65 and 80% indicating supporting evidence for no impact on OTC function (PMID: 37146589) (BS3_Supporting). The computational predictor REVEL gives a score of 0.57 which is between 0.644 and 0.290 and indicates an uncertain impact on OTC function. In summary, this variant meets the criteria to be classified as benign for OTC deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Urea Cycle Disorders Variant Curation Expert Panel (OTC specifications version 1.0.0): BA1, BS3_Supporting.

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

Computational evidence

Protein change
AlphaMissense	0.204	likely benign
REVEL	0.57	indeterminate
SaProt	LLR -7.39	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 0.61, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 68 kb · p 3.9e-05 · regional, not allelic
Overall
CADD	17.72	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 0.0109% Admixed American · 5/45,704 alleles

Filtering AF 0.00532% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00478%

Overall 0.00539% 65/1,205,859 alleles · ultra-rare exomes 59/1,094,009 · genomes 6/111,850 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0109%	9,141
European (non-Finnish)	0.00673%	14,858

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.Leu166Phe
Coding: c.498G>T
MANE Select: NM_000531
dbSNP: rs759911602
Type: single nucleotide variant
Location: chrX:38401386 (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 p.Leu166Ser Uncertain significance ★ ⚠ 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
OTC c.663+1G>T 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-leu166phe (accessed [today's date]).

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