USP53

Chr 4AR

ubiquitin specific peptidase 53

Also known as: PFIC7

NCBI Gene: 54532 ENSG00000145390 UniProt: Q70EK8 OMIM: 617431

USP53 encodes a deubiquitinase that cleaves K63-linked polyubiquitin chains from tight junction proteins, modulating barrier properties and mechanical stability of tight junctions. Mutations cause autosomal recessive progressive familial intrahepatic cholestasis type 7, which may be associated with hearing loss due to the protein's role in auditory hair cell survival. This gene is not highly constrained against loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Cholestasis, progressive familial intrahepatic, 7, with or without hearing lossMIM #619658

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Cholestasis, progressive familial intrahepatic, 7, with or without hearing loss; no ClinGen or GenCC tier

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.78

LOEUF

Mechanism· predicted

📖

GeneReview available — USP53

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.78LOEUF

pLI 0.000

Z-score 2.83

OE 0.57 (0.42–0.78)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.98Z-score

OE missense 0.88 (0.82–0.95)

496 obs / 561.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.57 (0.42–0.78)

0≤0.351.4

Missense OE?0.88 (0.82–0.95)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 29 / 50.7Missense obs/exp: 496 / 561.5Syn Z: 1.41

Background carrier burden — how many people carry a rare variant somewhere in USP53?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 40

1,278 rare PASS variants

Rare truncating (LoF)

1 in 590

252 rare PASS variants

Rare synonymous (reference)

1 in 120

390 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for USP53. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 64	1 in 700
South Asian	~43k	1 in 40	1 in 260
Remaining (unassigned)	~30k	1 in 38	1 in 940
European (Finnish)	~27k	1 in 120	1 in 2,800
Admixed American	~22k	1 in 46	1 in 400
African / African American	~21k	1 in 37	1 in 440
East Asian	~20k	1 in 58	1 in 370
Ashkenazi Jewish	~13k	1 in 280	≈ 1 in 3,800
Middle Eastern	~2,884	1 in 50	≈ 1 in 720

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 12 of 15 coding exons well covered in gnomAD exomes; exons 12, 15, 18 marginal. Genomes: 14 of 15 (exon 18 below).? see exons ↓