USP25

Chr 21AD

ubiquitin specific peptidase 25

Also known as: EIG19, USP21

NCBI Gene: 29761ENSG00000155313UniProt: Q9UHP3

Ubiquitin (MIM 191339) is a highly conserved 76-amino acid protein involved in regulation of intracellular protein breakdown, cell cycle regulation, and stress response. Ubiquitin is released from degraded proteins by disassembly of the polyubiquitin chains, which is mediated by ubiquitin-specific proteases (USPs), such as USP25 (Valero et al., 1999 [PubMed 10644437]).[supplied by OMIM, Mar 2008]

Primary Disease Associations & Inheritance

{Epilepsy, idiopathic generalized, susceptibility to, 19}MIM #621064
AD
205
ClinVar variants
71
Pathogenic / LP
0.75
pLI score
0
Active trials
Clinical Summary— USP25
🧬
Gene-Disease Validity (ClinGen)
epilepsy · ADDisputed

Disputed — evidence questions this relationship

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.75) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
71 Pathogenic / Likely Pathogenic· 129 VUS of 205 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.33LOEUF
pLI 0.752
Z-score 5.95
OE 0.21 (0.14–0.33)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
1.24Z-score
OE missense 0.85 (0.79–0.92)
453 obs / 533.4 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.0.21 (0.14–0.33)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.85 (0.79–0.92)
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.0.98
0≤1.21.6
LoF obs/exp: 14 / 66.3Missense obs/exp: 453 / 533.4Syn Z: 0.26

ClinVar Variant Classifications

205 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic69
Likely Pathogenic2
VUS129
Likely Benign4
Conflicting1
69
Pathogenic
2
Likely Pathogenic
129
VUS
4
Likely Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
69
0
69
Likely Pathogenic
0
0
2
0
2
VUS
0
118
11
0
129
Likely Benign
0
0
1
3
4
Benign
0
0
0
0
0
Conflicting
—1
Total0118833205

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

View in ClinVar →

Protein Context — Lollipop Plot

USP25 · 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

{Epilepsy, idiopathic generalized, susceptibility to, 19}

MIM #621064

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Expression of USP25 associates with fibrosis, inflammation and metabolism changes in IgG4-related disease.
Jiang P et al.·Nat Commun
2024
Heterozygous variants in USP25 cause genetic generalized epilepsy.
Fan CX et al.·Brain
2024
Ubiquitin-specific protease 25 ameliorates ulcerative colitis by regulating the degradation of phosphor-STAT3.
Liu Z et al.·Cell Death Dis
2025
USP25-driven KIFC1 regulates MYCBP expression and promotes the progression of cervical cancer.
Ye Z et al.·Cell Death Dis
2025
Ubiquitin-specific protease 25 improves myocardial ischemia-reperfusion injury by deubiquitinating NLRP3 and negatively regulating NLRP3 inflammasome activity in cardiomyocytes.
Ye B et al.·Clin Transl Med
2025
USP25 inhibition ameliorates Parkinson's disease by restoring mitophagy.
Xu Y et al.·Proc Natl Acad Sci U S A
2026
Usp25-Erlin1/2 activity limits cholesterol flux to restrict virus infection.
Teo QW et al.·Dev Cell
2023
Tim-3 promotes viral infection by suppressing the USP25-TRAF3-IRF7 signaling pathway.
Du L et al.·Cell Immunol
2025
Targeting deubiquitinating enzymes and ubiquitin pathway modulators to enhance host defense against bacterial infections.
Santelices J et al.·mBio
2025
USP28: Oncogene or Tumor Suppressor? A Unifying Paradigm for Squamous Cell Carcinoma.
Prieto-Garcia C et al.·Cells
2021Review
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