USP6

protein-coding

ubiquitin specific peptidase 6, the group of Ubiquitin specific peptidases

Gene summary

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]

Previous symbols:

HRP1
TRESMCR

MANE transcript

NM_001304284.2

Inheritance

—

ClinVar variants

U:197B:17

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.79

Max pathogenic AF

—

Genomic locus

chr17:5,116,032-5,175,034

External References & Databases

Ensembl (ENSG00000129204)

Transcript & Mutation Effects

hg38 • Region Span ~59.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to USP6 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 200

not providedTotal: 13

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001304284.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				4 clinvar	3 clinvar	7
missense			196 clinvar	7 clinvar	2 clinvar	205
nonsense						0
start loss						0
frameshift					1 clinvar	1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	197	11	6	214

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001304284.2	RefSeq	NP_001291213.1	29	MANE Select
ENST00000574788.6	Ensembl	ENSP00000460380.1	29	MANE Select
NM_004505.4	RefSeq	NP_004496.2	29	Standard
ENST00000250066.6	Ensembl	ENSP00000250066.6	29	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Arf6 signaling events

Biological Process

cellular protein modification process
ubiquitin-dependent protein catabolic process
intracellular protein transport
protein deubiquitination
regulation of vesicle-mediated transport

Molecular Function

nucleic acid binding
cysteine-type endopeptidase activity
thiol-dependent ubiquitin-specific protease activity
GTPase activator activity
protein binding

Cellular Component

cytoplasm
lysosome
plasma membrane
recycling endosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000574788
Coding exons: 29
Length: 58597
Individuals with no LoFs: 124183
Homozygous LoFs: 11
Heterozygous LoFs: 1554
Defined: 125748
p: 0.00624

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.142	792	781	1.01	0.0000439	9244
Missense (PolyPhen)		260	278.65	0.93308		3591
Synonymous	-0.495	299	288	1.04	0.0000165	2623
Loss of Function	1.74	63	79.8	0.790	0.00000455	867

Population LoF Frequency

Population	CAF	p-value	Status
African	0.043	0.043	notable
Latino/Admixed American	0.0081	0.0079	notable
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.0016	0.0015	notable
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.0036	0.0035	notable
South Asian	0.0051	0.0051	notable
Other	0.0047	0.0046	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Deubiquitinase with an ATP-independent isopeptidase activity, cleaving at the C-terminus of the ubiquitin moiety. Catalyzes its own deubiquitination. In vitro, isoform 2, but not isoform 3, shows deubiquitinating activity. Promotes plasma membrane localization of ARF6 and selectively regulates ARF6- dependent endocytic protein trafficking. Is able to initiate tumorigenesis by inducing the production of matrix metalloproteinases following NF-kappa-B activation. {ECO:0000269|PubMed:15509780, ECO:0000269|PubMed:16127172, ECO:0000269|PubMed:20418905}.;
Disease: DISEASE: Note=A chromosomal aberration involving USP6 is a common genetic feature of aneurysmal bone cyst, a benign osseous neoplasm. Translocation t(16;17)(q22;p13) with CDH11. The translocation generates a fusion gene in which the strong CDH11 promoter is fused to the entire USP6 coding sequence, resulting in USP6 transcriptional up-regulation (PubMed:15026324). {ECO:0000269|PubMed:15026324}.;

Intolerance Scores

LoFtool: 0.996
RVIS EVS: 0.42
RVIS percentile EVS: 76.96

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.423

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High