USP18

Chr 22AR

ubiquitin specific peptidase 18

Also known as: ISG43, PTORCH2, UBP43

NCBI Gene: 11274ENSG00000184979UniProt: Q9UMW8

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]

Primary Disease Associations & Inheritance

Pseudo-TORCH syndrome 2MIM #617397
AR
222
ClinVar variants
125
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— USP18
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
125 Pathogenic / Likely Pathogenic· 61 VUS of 222 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.74LOEUF
pLI 0.001
Z-score 2.41
OE 0.41 (0.24–0.74)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.84Z-score
OE missense 0.83 (0.73–0.94)
158 obs / 190.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.41 (0.24–0.74)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.83 (0.73–0.94)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.02
0≤1.21.6
LoF obs/exp: 8 / 19.5Missense obs/exp: 158 / 190.7Syn Z: -0.14

ClinVar Variant Classifications

222 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic119
Likely Pathogenic6
VUS61
Likely Benign16
Benign10
Conflicting2
119
Pathogenic
6
Likely Pathogenic
61
VUS
16
Likely Benign
10
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
119
0
119
Likely Pathogenic
2
0
4
0
6
VUS
0
45
16
0
61
Likely Benign
0
7
1
8
16
Benign
0
3
5
2
10
Conflicting
—2
Total25514510214

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

USP18 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

USP18-related severe pseudo-TORCH syndrome

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Pseudo-TORCH syndrome 2

MIM #617397

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A commonly inherited human PCSK9 germline variant drives breast cancer metastasis via LRP1 receptor.
Mei W et al.·Cell
2025
Regulation of STING activity in DNA sensing by ISG15 modification.
Lin C et al.·Cell Rep
2023
Exploring the shared molecular mechanisms between systemic lupus erythematosus and primary Sjögren's syndrome based on integrated bioinformatics and single-cell RNA-seq analysis.
Cui Y et al.·Front Immunol
2023Functional
USP18 Is Associated with PD-L1 Antitumor Immunity and Improved Prognosis in Colorectal Cancer.
Jifu C et al.·Biomolecules
2024
Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation.
Zhang X et al.·Nature
2015
LncRNA BCCE4 Genetically Enhances the PD-L1/PD-1 Interaction in Smoking-Related Bladder Cancer by Modulating miR-328-3p-USP18 Signaling.
Zheng R et al.·Adv Sci (Weinh)
2023
Microglial Interferon Signaling and White Matter.
McDonough A et al.·Neurochem Res
2017Review
Deubiquitinase USP18 mediates cell migration, apoptosis and ferroptosis in lung adenocarcinoma by depending on POU4F1/PRKAA2 axis.
Pan X et al.·BMC Cancer
2025
USP18 reduces paclitaxol sensitivity of triple-negative breast cancer via autophagy.
Ge X et al.·Biochem Biophys Res Commun
2022
USP18 orchestrates malignant progression in nasopharyngeal carcinoma through UBR5-driven attenuation of p53 signaling.
Yi Q et al.·Int Immunopharmacol
2026Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools