ZUP1

Chr 6

zinc finger containing ubiquitin peptidase 1

Also known as: C6orf113, DUB, ZUFSP

NCBI Gene: 221302ENSG00000153975UniProt: Q96AP4

This gene encodes a protein containing zinc finger motifs and a cysteine peptidase domain. The encoded protein functions as a K63-specific de-ubiquitinating enzyme that specifically cleaves long K63-linked polyubiquitin chains in the middle of a chain (i.e. "endo cleavage) rather than by removing the terminal ubiquitin from a chain. This enzyme is thought to be involved in the regulation of DNA repair by cleaving K63-linked ubiquitin chains at repair foci. This protein is related to proteases for the ubiquitin-like modifiers Ufm1 (ubiquitin fold modifier 1) and Atg8/Gabarapl2, but does not have any activity on these modifiers. [provided by RefSeq, Mar 2018]

104
ClinVar variants
29
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ZUP1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
29 Pathogenic / Likely Pathogenic· 73 VUS of 104 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.
0.96LOEUF
pLI 0.000
Z-score 1.73
OE 0.65 (0.45–0.96)
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.
0.08Z-score
OE missense 0.99 (0.90–1.09)
286 obs / 289.9 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.0.65 (0.45–0.96)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.99 (0.90–1.09)
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.1.03
0≤1.21.6
LoF obs/exp: 18 / 27.9Missense obs/exp: 286 / 289.9Syn Z: -0.25

ClinVar Variant Classifications

104 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25
Likely Pathogenic4
VUS73
Likely Benign2
25
Pathogenic
4
Likely Pathogenic
73
VUS
2
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
24
0
25
Likely Pathogenic
0
0
4
0
4
VUS
0
67
6
0
73
Likely Benign
0
2
0
0
2
Benign
0
0
0
0
0
Total169340104

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

View in ClinVar →

Protein Context — Lollipop Plot

ZUP1 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
ZUP1 is a key component of the MAVS complex and acts as a protector of host against viral invasion.
Hao W et al.·FASEB J
2025
A structural basis for the diverse linkage specificities within the ZUFSP deubiquitinase family.
Hermanns T et al.·Nat Commun
2022
Reactive-site-centric chemoproteomics identifies a distinct class of deubiquitinase enzymes.
Hewings DS et al.·Nat Commun
2018
MAVS promotes interferon signaling in RNA virus infection by ZUFSP-mediated chromatin regulation.
Li T et al.·Int Immunopharmacol
2024
Friend or Foe: UCHL3 Mediated Carcinogenesis and Current Approaches in Small Molecule Inhibitors' Development.
Samy MA et al.·Curr Med Chem
2021Review
ZUFSP Deubiquitylates K63-Linked Polyubiquitin Chains to Promote Genome Stability.
Haahr P et al.·Mol Cell
2018
A family of unconventional deubiquitinases with modular chain specificity determinants.
Hermanns T et al.·Nat Commun
2018
Discovery and Characterization of ZUFSP/ZUP1, a Distinct Deubiquitinase Class Important for Genome Stability.
Kwasna D et al.·Mol Cell
2018
Functional Analysis of Single Nucleotide Polymorphism in ZUFSP Protein and Implication in Pathogenesis.
Ajadi MB et al.·Protein J
2021Functional
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