Is OTC p.Pro319Ser (c.955C>T) pathogenic?

OTC p.Pro319Ser (c.955C>T) is classified Uncertain significance in OTC (ClinVar, Single submitter, 2 submitters; last evaluated 2023-03-04). AlphaMissense: likely benign (0.1027); Very rare (popmax 0.00352%, sas); Associated with ornithine carbamoyltransferase deficiency.

What condition is associated with OTC p.Pro319Ser (c.955C>T)?

OTC p.Pro319Ser (c.955C>T) is associated with ornithine carbamoyltransferase deficiency (ClinVar).

How common is OTC p.Pro319Ser (c.955C>T) in the general population?

OTC p.Pro319Ser (c.955C>T) is very rare (popmax 0.00352%, sas) (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.Pro319Ser (c.955C>T)?

AlphaMissense predicts likely benign (score 0.1027) — an in-silico prediction, not a clinical call.

OTC p.Pro319Ser

c.955C>T · rs372070932 · VCV3069748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1027 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00352%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ornithine carbamoyltransferase deficiency

Computational evidence

Protein change
AlphaMissense	0.1027	likely benign
REVEL	0.649	pathogenic-leaning
SaProt	LLR -8.56	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.7	GERP 1.3, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 68 kb · p 3.9e-05 · regional, not allelic
Overall
CADD	14.27	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 0.00352% South Asian · 2/56,766 alleles

Filtering AF 0.000584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000219%

Overall 0.000248% 3/1,207,583 alleles · very rare exomes 2/1,095,579 · genomes 1/112,004 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00352%	28,383
European (non-Finnish)	0.000112%	893,001

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.Pro319Ser
Coding: c.955C>T
MANE Select: NM_000531
dbSNP: rs372070932
Type: single nucleotide variant
Location: chrX:38411949 (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.Pro319del 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-pro319ser (accessed [today's date]).

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