ISG15
Chr 1ARISG15 ubiquitin like modifier
Also known as: G1P2, IFI15, IMD38, IP17, UCRP, hUCRP
The encoded protein is a ubiquitin-like modifier that conjugates to target proteins (ISGylation) and functions as a secreted cytokine, both critical for antiviral immunity and interferon signaling. Mutations cause immunodeficiency 38, an autosomal recessive primary immunodeficiency characterized by increased susceptibility to viral infections and mycobacterial disease. The gene shows moderate tolerance to loss-of-function variants (LOEUF 1.691), consistent with the recessive inheritance pattern where biallelic mutations are required for disease.
Primary Disease Associations & Inheritance
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Tolerant to missense variation
The highest-scoring mechanism for this gene is dominant-negative.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
304 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 1 | 0 | 118 | 0 | 119 |
Likely Pathogenic | 1 | 0 | 6 | 0 | 7 |
VUS | 5 | 62 | 25 | 0 | 92 |
Likely Benign | 0 | 3 | 11 | 50 | 64 |
Benign | 0 | 1 | 8 | 6 | 15 |
Conflicting | — | 6 | |||
| Total | 7 | 66 | 168 | 56 | 303 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
ISG15 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Comparing Immune Activation and Latent HIV Reservoir Size Between People Living With HIV on Tenofovir-containing Versus NRTI-free ART
ENROLLING BY INVITATIONMolecular Biological and Moleculargenetic Monitoring of Therapy After Kidney Transplantation
RECRUITINGExternal Resources
Links to major genomics databases and tools