Is OTC p.Arg129His (c.386G>A) pathogenic?

OTC p.Arg129His (c.386G>A) is classified Pathogenic in OTC (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-10-03). AlphaMissense: likely benign (0.1945); Absent from gnomAD v4.1; Associated with ornithine carbamoyltransferase deficiency.

What condition is associated with OTC p.Arg129His (c.386G>A)?

OTC p.Arg129His (c.386G>A) is associated with ornithine carbamoyltransferase deficiency (ClinVar).

How common is OTC p.Arg129His (c.386G>A) in the general population?

OTC p.Arg129His (c.386G>A) 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.Arg129His (c.386G>A)?

AlphaMissense predicts likely benign (score 0.1945) — an in-silico prediction, not a clinical call.

OTC p.Arg129His

c.386G>A · rs66656800 · VCV11010

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1945 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,158,972)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ornithine carbamoyltransferase deficiency

Computational evidence

Protein change
AlphaMissense	0.1945	likely benign ⚠ discordant with ClinVar
REVEL	0.909	moderately pathogenic-leaning
SaProt	LLR -8.83	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.91	donor loss · deltas
Pangolin	Δ0.73	loss · gain 0.29 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 68 kb · p 3.9e-05 · regional, not allelic
Overall
CADD	34.0	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

No allele count reported in gnomAD v4.1 (AN 1,158,972). 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.Arg129His
Coding: c.386G>A
MANE Select: NM_000531
dbSNP: rs66656800
Type: single nucleotide variant
Location: chrX:38381429 (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)

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.Arg129Cys Uncertain significance ★★ ⚠ same residue
OTC p.Arg129= Conflicting classifications of pathogenicity ★ 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-arg129his (accessed [today's date]).

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