USP53
Chr 4ARubiquitin specific peptidase 53
Also known as: PFIC7
USP53 encodes a deubiquitinase that cleaves K63-linked polyubiquitin chains from tight junction proteins, modulating barrier properties and mechanical stability of tight junctions. Mutations cause autosomal recessive progressive familial intrahepatic cholestasis type 7, which may be associated with hearing loss due to the protein's role in auditory hair cell survival. This gene is not highly constrained against loss-of-function variants.
Primary Disease Associations & Inheritance
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
300 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 | 12 | 2 | 25 | 0 | 39 |
Likely Pathogenic | 12 | 3 | 8 | 0 | 23 |
VUS | 1 | 130 | 9 | 1 | 141 |
Likely Benign | 0 | 10 | 13 | 24 | 47 |
Benign | 0 | 9 | 5 | 8 | 22 |
Conflicting | — | 7 | |||
| Total | 25 | 154 | 60 | 33 | 279 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
USP53 · 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
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools