Is OTC p.Ser81Pro (c.241T>C) pathogenic?

OTC p.Ser81Pro (c.241T>C) is classified Pathogenic/Likely pathogenic in OTC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-02). AlphaMissense: likely pathogenic (0.9385); Absent from gnomAD v4.1; Associated with ornithine carbamoyltransferase deficiency.

What condition is associated with OTC p.Ser81Pro (c.241T>C)?

OTC p.Ser81Pro (c.241T>C) is associated with ornithine carbamoyltransferase deficiency (ClinVar).

How common is OTC p.Ser81Pro (c.241T>C) in the general population?

OTC p.Ser81Pro (c.241T>C) 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.Ser81Pro (c.241T>C)?

AlphaMissense predicts likely pathogenic (score 0.9385) — an in-silico prediction, not a clinical call.

OTC p.Ser81Pro

c.241T>C · rs2147324956 · VCV1504390

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9385 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ornithine carbamoyltransferase deficiency

ClinGen expert panel — Urea Cycle Disorders VCEP

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

PP3_Moderate PM2_Supporting PS2 PP4

Curation rationale (ClinGen, verbatim)

The NM_000531.6(OTC):c.241T>C variant in OTC is a missense variant predicted to cause substitution of serine by proline at amino acid 81 (p.Ser81Pro). This variant has been reported as a de novo variant (confirmed by parental testing) in one (hemizygous) male individual with biochemical evidence of OTC deficiency (elevated ammonia, normal citrulline, and elevated urine uracil) (PS2, PP4) (PMID: 38802913). It has also been reported in 1 heterozygous female with elevated ammonia without further biochemical testing reported (PMID: 32447331), such that this individual cannot be counted for PP4 and/or PS4 as per UCD VCEP specifications. This variant is absent in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.854, which is between 0.773 and 0.932, and Moderate evidence of impact on OTC/NAGS/CPS1 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic 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): PS2, PM2_Supporting, PP3, PP4.

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

Computational evidence

Protein change
AlphaMissense	0.9385	likely pathogenic ✓ concordant with ClinVar
REVEL	0.854	moderately pathogenic-leaning
SaProt	LLR -13.47	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.3	GERP -0.039, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 68 kb · p 3.9e-05 · regional, not allelic
Overall
CADD	23.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: OTC
Protein: p.Ser81Pro
Coding: c.241T>C
MANE Select: NM_000531
dbSNP: rs2147324956
Type: single nucleotide variant
Location: chrX:38369820 (GRCh38)
Structure: AlphaFold pLDDT 91.94 · 4 PDB
Residue 81: a β-strand

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.Ser81Phe Uncertain significance ★★ ⚠ same residue
OTC p.Ser81= Likely benign ★ 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

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-ser81pro (accessed [today's date]).

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