USP18

Chr 22AR

ubiquitin specific peptidase 18

Also known as: ISG43, PTORCH2, UBP43

NCBI Gene: 11274 ENSG00000184979 UniProt: Q9UMW8 OMIM: 607057

USP18 encodes an interferon-induced protease that cleaves ISG15 conjugates from proteins and negatively regulates type I interferon signaling pathways. Mutations cause pseudo-TORCH syndrome 2, an autosomal recessive disorder characterized by early-onset neurologic abnormalities that can mimic congenital infections. The gene shows tolerance to loss-of-function variants (low pLI), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to the ubiquitin-specific proteases (UBP) family of enzymes that cleave ubiquitin from ubiquitinated protein substrates. It is highly expressed in liver and thymus, and is localized to the nucleus. This protein efficiently cleaves only ISG15 (a ubiquitin-like protein) fusions, and deletion of this gene in mice results in a massive increase of ISG15 conjugates in tissues, indicating that this protein is a major ISG15-specific protease. Mice lacking this gene are also hypersensitive to interferon, suggesting a function of this protein in downregulating interferon responses, independent of its isopeptidase activity towards ISG15. [provided by RefSeq, Sep 2011]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Pseudo-TORCH syndrome 2MIM #617397

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

106

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.74

LOEUF

LOF

Mechanism· G2P