USP8

Chr 15

ubiquitin specific peptidase 8

Also known as: HumORF8, PITA4, SPG59, UBPY

NCBI Gene: 9101 ENSG00000138592 UniProt: P40818

The protein functions as a deubiquitinating enzyme that removes ubiquitin from target proteins, regulating endosomal trafficking, cargo sorting, and cell cycle progression. Mutations cause pituitary adenoma 4 (ACTH-secreting), which follows a somatic inheritance pattern. The gene is highly constrained against loss-of-function variants (pLI >0.99), suggesting that germline mutations would likely be severe.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that belongs to the ubiquitin-specific processing protease family of proteins. The encoded protein is thought to regulate the morphology of the endosome by ubiquitination of proteins on this organelle and is involved in cargo sorting and membrane trafficking at the early endosome stage. This protein is required for the cell to enter the S phase of the cell cycle and also functions as a positive regulator in the Hedgehog signaling pathway in development. Pseudogenes of this gene are present on chromosomes 2 and 6. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtPituitary adenoma 4, ACTH-secreting

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

107

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.11

LOEUF· LoF intol.

—

Mechanism

📖

GeneReview available — USP8

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.11LOEUF

pLI 1.000

Z-score 6.66

OE 0.04 (0.01–0.11)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

1.87Z-score

OE missense 0.78 (0.72–0.84)

439 obs / 563.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.11)

0≤0.351.4

Missense OE?0.78 (0.72–0.84)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 2 / 55.6Missense obs/exp: 439 / 563.7Syn Z: 1.00

Background carrier burden — how many people carry a rare variant somewhere in USP8?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 66

1,122 rare PASS variants

Rare truncating (LoF)

1 in 1,300

95 rare PASS variants

Rare synonymous (reference)

1 in 110

408 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for USP8. 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 120	1 in 1,300
South Asian	~43k	1 in 73	1 in 730
Remaining (unassigned)	~30k	1 in 50	1 in 2,300
European (Finnish)	~27k	1 in 210	1 in 3,800
Admixed American	~22k	1 in 59	1 in 700
African / African American	~21k	1 in 64	1 in 2,400
East Asian	~20k	1 in 44	≈ 1 in 6,500
Ashkenazi Jewish	~13k	1 in 540	1 in 2,500
Middle Eastern	~2,884	1 in 75	≈ 1 in 930

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): 16 of 19 coding exons well covered in gnomAD exomes; exons 2, 4, 13 marginal. Genomes: all 19.? see exons ↓