USP53

protein-coding

ubiquitin specific peptidase 53, the group of Ubiquitin specific peptidases

Gene summary

Enables K63-linked deubiquitinase activity. Predicted to be involved in response to auditory stimulus and sensory perception of sound. Predicted to act upstream of or within action potential and neuron apoptotic process. Located in bicellular tight junction. Implicated in progressive familial intrahepatic cholestasis. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_001371395.1

Inheritance

ClinVar variants

P:40U:146B:53

Top phenotype

Cholestasis, progressive familial intrahepatic, 7, with or without hearing loss

gnomAD constraint

pLI —, LoF o/e 0.57

Max pathogenic AF

—

Genomic locus

chr4:119,212,587-119,295,518

External References & Databases

Ensembl (ENSG00000145390)

Transcript & Mutation Effects

hg38 • Region Span ~82.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cholestasis, progressive familial intrahepatic, 7, with or without hearing lossSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030503

Submitter: Labcorp Genetics (formerly Invitae)

cholestasis, progressive familial intrahepatic, 7, with or without hearing lossSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030503

Submitter: PanelApp Australia

cholestasisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0001751

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Cholestasis, progressive familial intrahepatic, 7, with or without hearing lossAR

Manifestation: Audiologic/Otolaryngologic; Gastrointestinal

Intervention: Audiologic/Otolaryngologic; Gastrointestinal

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Rifampicin has been described as effective for pruritis; Medical management has been described as beneficial as pertains to cholestasis and related sequelae; Liver transplant has been described

Refs: 30250217; 32124521; 33075013

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to USP53 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 121

not providedTotal: 103

Cholestasis, progressive familial intrahepatic, 7, with or without hearing lossTotal: 39

CholestasisTotal: 10

USP53-related disorderTotal: 4

Premature ovarian insufficiencyTotal: 3

Cholestasis, progressive familial intrahepatic, (PFIC4-like)Total: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001371395.1. 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			2 clinvar	25 clinvar	5 clinvar	32
missense	2 clinvar	3 clinvar	136 clinvar	16 clinvar	7 clinvar	164
nonsense	5 clinvar	6 clinvar	1 clinvar			12
start loss						0
frameshift	11 clinvar	5 clinvar				16
splice donor/acceptor (+/-2bp)	2 clinvar	6 clinvar	7 clinvar			15
Total	20	20	146	41	12	239

Highest pathogenic variant AF is 0.000066961475

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 58 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001371395.1	RefSeq	NP_001358324.1	15	MANE Select
ENST00000692078.1	Ensembl	ENSP00000509606.1	15	MANE Select
NM_001371396.1	RefSeq	NP_001358325.1	14	Standard
NM_001371397.1	RefSeq	NP_001358326.1	14	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
usp53a	Danio rerio	Structure: post-vent region Quality: curled abnormal

Gene / Model

Organism

Observed Phenotype

usp53a

Danio rerio

Structure: post-vent region

Quality: curled

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

action potential
sensory perception of sound
biological_process
response to auditory stimulus
protein deubiquitination

Molecular Function

protein binding
thiol-dependent ubiquitinyl hydrolase activity

Cellular Component

cellular_component
bicellular tight junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000450251
Coding exons: 15
Length: 82931
Individuals with no LoFs: 124685
Homozygous LoFs: 0
Heterozygous LoFs: 108
Defined: 124793
p: 0.000433

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.982	496	562	0.883	0.0000280	7162
Missense (PolyPhen)		155	184.4	0.84055		2297
Synonymous	1.41	165	190	0.870	0.00000923	1924
Loss of Function	2.83	29	50.8	0.571	0.00000287	628

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00045	0.00045	rare
Latino/Admixed American	0.00061	0.00061	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00072	0.00072	rare
Finnish	0.000093	0.000093	rare
European (Non-Finnish)	0.00034	0.00034	rare
South Asian	0.00089	0.00088	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Tight junction-associated protein that is involved in the survival of auditory hair cells and hearing. Maybe by modulating the barrier properties and mechanical stability of tight junctions (By similarity). Has no peptidase activity (PubMed:14715245). {ECO:0000250|UniProtKB:P15975, ECO:0000269|PubMed:14715245}.;

Recessive Scores

pRec: 0.103

Intolerance Scores

LoFtool: 0.913
RVIS EVS: 0.83
RVIS percentile EVS: 88.11

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.812

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium