OTC p.Arg129=
c.387T>C · rs1052206430 · VCV1915613
ClinGen expert panel — Urea Cycle Disorders VCEP
Uncertain Significance for ornithine carbamoyltransferase deficiency. Applied ACMG criteria (verbatim):
PM2_Supporting BP7 BP4
Curation rationale (ClinGen, verbatim)
The NM_000531.6:c.387T>C variant in OTC is a synonymous (silent) variant (p.Arg129_Val130=) that is not predicted by SpliceAI to impact splicing and the nucleotide (BP4), however the nucleotide is within the first 3 bases of an exon, so BP7 is not applicable. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. Grpmax MAF in gnomAD v4.1.0 is 0.000009190 in the European (non-Finnish) population which is lower than the ClinGen UCD VCEP’s threshold for PM2_Supporting (<0.000015) and there are ≤1 hemizygotes/homozygotes across all populations, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance 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): BP4, 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. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 0.014 | GERP -2.9, phastCons 0.92 |
| Overall | ||
| CADD | 10.31 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
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.Arg129=
- Coding
- c.387T>C
- MANE Select
- NM_000531
- dbSNP
- rs1052206430
- Type
- single nucleotide variant
- Location
- chrX:38401275 (GRCh38)
- Structure
- AlphaFold pLDDT 91.94 · 4 PDB
- Residue 129
- an α-helix; a UniProt-annotated variant site (in otcd; early onset; decreased ornithine carbamoyltransferase activity; 2.1% of wild-type activity)
Disease context
ornithine carbamoyltransferase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsFor Ornithine transcarbamylase deficiency (Orphanet):
- Inheritance
- X-linked recessive
- Onset
- All ages
- Prevalence
- 1-9 / 100 000 (Europe)
Similar variants
- OTC p.Arg129His Pathogenic ★★ ⚠ same residue
- OTC p.Arg129Cys Uncertain significance ★★ ⚠ same residue
- OTC p.Arg129Leu Pathogenic same residue
- OTC p.Arg129Pro 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
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-arg129 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown