Is OTC p.Phe48Ser (c.143T>C) pathogenic?

OTC p.Phe48Ser (c.143T>C) is classified Pathogenic in OTC (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9435); Very rare (popmax 8.32e-05%).

How common is OTC p.Phe48Ser (c.143T>C) in the general population?

OTC p.Phe48Ser (c.143T>C) is very rare (popmax 8.32e-05%) (gnomAD).

What do computational predictors say about OTC p.Phe48Ser (c.143T>C)?

AlphaMissense predicts likely pathogenic (score 0.9435) — an in-silico prediction, not a clinical call.

OTC p.Phe48Ser

c.143T>C · rs72554315 · VCV97115

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9435 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.32e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9435	likely pathogenic ✓ concordant with ClinVar
REVEL	0.778	moderately pathogenic-leaning
SaProt	LLR -11.25	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 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 68 kb · p 3.9e-05 · regional, not allelic
Overall
CADD	25.6	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 8.32e-05%

Overall 8.32e-05% 1/1,201,990 alleles · very rare exomes 1/1,089,036 · genomes 0/112,954 · joint denominator

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.Phe48Ser
Coding: c.143T>C
MANE Select: NM_000531
dbSNP: rs72554315
Type: single nucleotide variant
Location: chrX:38367356 (GRCh38)
Structure: AlphaFold pLDDT 91.94 · 4 PDB

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

Similar variants

OTC p.Phe48= Likely benign ★ same residue
OTC p.Phe48fs Likely pathogenic ★ same residue
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

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-phe48ser (accessed [today's date]).

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