Is OTC p.Ala128Pro (c.382G>C) pathogenic?

OTC p.Ala128Pro (c.382G>C) is classified Uncertain significance in OTC (ClinVar, Single submitter, 1 submitter; last evaluated 2016-03-25). AlphaMissense: likely pathogenic (0.9811); Absent from gnomAD v4.1.

How common is OTC p.Ala128Pro (c.382G>C) in the general population?

OTC p.Ala128Pro (c.382G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about OTC p.Ala128Pro (c.382G>C)?

AlphaMissense predicts likely pathogenic (score 0.9811) — an in-silico prediction, not a clinical call.

OTC p.Ala128Pro

c.382G>C · rs886043507 · VCV286877

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9811 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9811	likely pathogenic · top 8% in OTC
REVEL	0.941	strongly pathogenic-leaning
SaProt	LLR -16.65	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 8.1	GERP 1.3, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 68 kb · p 3.9e-05 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Ala128Pro
Coding: c.382G>C
MANE Select: NM_000531
dbSNP: rs886043507
Type: single nucleotide variant
Location: chrX:38381425 (GRCh38)
Structure: AlphaFold pLDDT 91.94 · 4 PDB
Residue 128: an α-helix

Full OTC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

OTC c.298+2T>G Pathogenic ★★ same type
OTC c.299-1G>A Likely pathogenic ★★ same type
OTC c.386+1G>A Pathogenic ★★ same type
OTC c.540+1G>A Pathogenic ★★ same type
OTC c.540+1G>T Pathogenic ★★ same type
OTC c.540+265G>A Pathogenic ★★ same type
OTC c.663+1G>T Pathogenic ★★ same type
OTC c.663+2T>C Pathogenic ★★ same type

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-ala128pro (accessed [today's date]).

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