USP6

Chr 17

ubiquitin specific peptidase 6

Also known as: HRP1, TRE17, TRE2, TRESMCR, Tre-2, USP6-short

NCBI Gene: 9098ENSG00000129204UniProt: P35125

Enables cysteine-type deubiquitinase activity. Involved in protein deubiquitination and regulation of postsynaptic neurotransmitter receptor internalization. Located in plasma membrane and recycling endosome. Is active in glutamatergic synapse and postsynaptic density, intracellular component. [provided by Alliance of Genome Resources, Jul 2025]

243
ClinVar variants
23
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— USP6
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
23 Pathogenic / Likely Pathogenic· 201 VUS of 243 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.
0.97LOEUF
pLI 0.000
Z-score 1.74
OE 0.79 (0.64–0.97)
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.
-0.14Z-score
OE missense 1.01 (0.96–1.08)
792 obs / 780.8 exp
Tolerant

Tolerant to missense variation

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.0.79 (0.64–0.97)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.01 (0.96–1.08)
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.1.04
0≤1.21.6
LoF obs/exp: 63 / 79.8Missense obs/exp: 792 / 780.8Syn Z: -0.50

ClinVar Variant Classifications

243 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21
Likely Pathogenic2
VUS201
Likely Benign12
Benign7
21
Pathogenic
2
Likely Pathogenic
201
VUS
12
Likely Benign
7
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
21
0
21
Likely Pathogenic
0
0
2
0
2
VUS
0
192
9
0
201
Likely Benign
0
7
1
4
12
Benign
1
2
1
3
7
Total1201347243

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

View in ClinVar →

Protein Context — Lollipop Plot

USP6 · 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
Pediatric Bone Tumors.
Alston ELJ et al.·Surg Pathol Clin
2025Review
Multimodality imaging features of USP6-associated neoplasms.
Broski SM et al.·Skeletal Radiol
2023Review
Ubiquitin-specific Peptidase 6 (USP6)-associated Fibroblastic/Myofibroblastic Tumors: Evolving Concepts.
Nakayama S et al.·Cancer Genomics Proteomics
2021Review
USP6-Associated Neoplasms: A Rapidly Expanding Family of Lesions.
Hiemcke-Jiwa LS et al.·Int J Surg Pathol
2020Review
USP6 rearrangement in pediatric nodular fasciitis.
Sennett R et al.·J Cutan Pathol
2022Review
Novel ASAP1-USP6, FAT1-USP6, SAR1A-USP6, and TNC-USP6 fusions in primary aneurysmal bone cyst.
Šekoranja D et al.·Genes Chromosomes Cancer
2020
Giant Cell-Rich Tumors of Bone.
Hartmann W et al.·Surg Pathol Clin
2021Review
Unusual fusion gene rearrangements in patients with nodular fasciitis: a study of rare and novel USP6 fusion partners with a review of the literature.
Balko J et al.·J Clin Pathol
2024Review
Unravelling the USP6 gene: an update.
Cordier F et al.·J Clin Pathol
2023
Fibroma of Tendon Sheath Revisited.
Shinohara Y et al.·In Vivo
2025Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Clinical and Pathologic Description of Three Aneurysmal Bone Cyst Cases With Novel USP6 Fusion Partners Including SEC24D, HNRNPC, and ERRFI1.
Blackburn PR et al.·Genes Chromosomes Cancer
2025Cohort
A morphomolecular study of 175 'USP6-associated neoplasms': The USP6 fusion partner strongly depends on morphology and location.
Cordier F et al.·Histopathology
2026
Ubiquitin-Specific Protease 6 mRNA Lipid Nanoparticles Ignite Antitumor Immunity and Suppress Tumorigenesis in Ewing Sarcoma.
Henrich IC et al.·Mol Cancer Ther
2025
Deubiquitinase USP6 stabilizes oncogenic RUNX1 fusion proteins to promote the leukemic potential and malignant progression.
Zhang X et al.·Leukemia
2025
A Unique Case of Pediatric Orbital Nodular Fasciitis with a Confirmed USP6 Fusion Mutation.
Frauches RL et al.·Ophthalmic Plast Reconstr Surg
2026
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