Is OTC p.Leu124= (c.372C>T) pathogenic?

OTC p.Leu124= (c.372C>T) is classified Likely benign in OTC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-01). Very rare (popmax 0.0045%, nfe); Associated with ornithine carbamoyltransferase deficiency.

What condition is associated with OTC p.Leu124= (c.372C>T)?

OTC p.Leu124= (c.372C>T) is associated with ornithine carbamoyltransferase deficiency (ClinVar).

How common is OTC p.Leu124= (c.372C>T) in the general population?

OTC p.Leu124= (c.372C>T) is very rare (popmax 0.0045%, nfe) (gnomAD).

How is Ornithine transcarbamylase deficiency inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

OTC p.Leu124=

c.372C>T · rs201070935 · VCV735679

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0045%, nfe)

Conditions

ornithine carbamoyltransferase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 1.4, phastCons 1
Overall
CADD	6.719	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0045% European (non-Finnish) · 39/866,827 alleles

Filtering AF 0.00337% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00296%

Overall 0.00382% 45/1,178,338 alleles · very rare exomes 39/1,066,962 · genomes 6/111,376 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0108%	9,276
European (non-Finnish)grpmax	0.0045%	22,226
Remaining individualsnot grpmax-eligible	0.00215%	46,592

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu124=
Coding: c.372C>T
MANE Select: NM_000531
dbSNP: rs201070935
Type: single nucleotide variant
Location: chrX:38381415 (GRCh38)
Structure: AlphaFold pLDDT 91.94 · 4 PDB
Residue 124: 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.Leu124Phe 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-leu124 (accessed [today's date]).

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