Is USP18 p.Pro120Ser (c.358C>T) pathogenic?

USP18 p.Pro120Ser (c.358C>T) is classified Uncertain significance in USP18 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-13). AlphaMissense: likely pathogenic (0.696); Very rare (popmax 0.00134%, afr); Associated with pseudo-TORCH syndrome 2.

What condition is associated with USP18 p.Pro120Ser (c.358C>T)?

USP18 p.Pro120Ser (c.358C>T) is associated with pseudo-TORCH syndrome 2 (ClinVar).

How common is USP18 p.Pro120Ser (c.358C>T) in the general population?

USP18 p.Pro120Ser (c.358C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Pseudo-TORCH syndrome type 2 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about USP18 p.Pro120Ser (c.358C>T)?

AlphaMissense predicts likely pathogenic (score 0.696) — an in-silico prediction, not a clinical call.

USP18 p.Pro120Ser

c.358C>T · VCV3767287

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.696 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pseudo-TORCH syndrome 2

Computational evidence

Protein change
AlphaMissense	0.696	likely pathogenic
REVEL	0.267	benign-leaning
SaProt	LLR -12.24	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 10 kb · p 0.0088 · regional, not allelic
Overall
CADD	25.7	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 0.00134% African / African-American · 1/74,884 alleles

Overall 0.000496% 8/1,613,926 alleles · very rare exomes 4/1,461,778 · genomes 4/152,148 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0109%	9,147
African / African-Americangrpmax	0.00134%	74,884

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: USP18
Protein: p.Pro120Ser
Coding: c.358C>T
MANE Select: NM_017414
Type: single nucleotide variant
Location: chr22:18161893 (GRCh38)
Gene constraint: LOEUF 0.459 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.60 · 2 PDB
Residue 120: the usp domain

Full USP18 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pseudo-TORCH syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Pseudo-TORCH syndrome type 2 (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal

Similar variants

USP18 c.891+1G>T Likely pathogenic ★ same condition
USP18 p.Arg258Ter Pathogenic ★ same condition
USP18 p.Gln218Ter Likely pathogenic ★ same condition
USP18 p.Glu303Lys Conflicting classifications of pathogenicity ★ ⚠ same condition
USP18 c.1073+1G>A Pathogenic/Likely pathogenic same condition
USP18 p.Ser2Asn Uncertain significance ★★ ⚠ same type
USP18 p.Thr80Ile Uncertain significance ★★ ⚠ same type
USP18 c.158-5T>G Benign/Likely benign ★★ 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/usp18-p-pro120ser (accessed [today's date]).

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