USP40

Chr 2

ubiquitin specific peptidase 40

NCBI Gene: 55230 ENSG00000085982 UniProt: Q9NVE5 OMIM: 610570

USP40 encodes a deubiquitinating enzyme that maintains endothelial cell barrier integrity by stabilizing tight junction proteins like Claudin-1, regulates apoptosis through CFLAR stabilization, and suppresses inflammation by inhibiting NF-kappa-B activation. Mutations cause a neurodevelopmental disorder with intellectual disability, developmental delay, and seizures, inherited in an autosomal recessive pattern. The gene shows minimal constraint against loss-of-function variants, consistent with recessive inheritance where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, UniProt

Modification of cellular proteins by ubiquitin is an essential regulatory mechanism controlled by the coordinated action of multiple ubiquitin-conjugating and deubiquitinating enzymes. USP40 belongs to a large family of cysteine proteases that function as deubiquitinating enzymes (Quesada et al., 2004 [PubMed 14715245]).[supplied by OMIM, Mar 2008]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.93

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.93LOEUF

pLI 0.000

Z-score 2.06

OE 0.73 (0.58–0.93)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.24Z-score

OE missense 0.97 (0.91–1.04)

611 obs / 628.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.73 (0.58–0.93)

0≤0.351.4

Missense OE?0.97 (0.91–1.04)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 49 / 67.2Missense obs/exp: 611 / 628.0Syn Z: 0.33

Background carrier burden — how many people carry a rare variant somewhere in USP40?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 30

1,623 rare PASS variants

Rare truncating (LoF)

1 in 260

336 rare PASS variants

Rare synonymous (reference)

1 in 65

543 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for USP40. 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 41	1 in 260
South Asian	~43k	1 in 29	1 in 340
Remaining (unassigned)	~30k	1 in 29	1 in 200
European (Finnish)	~27k	1 in 150	1 in 1,300
Admixed American	~22k	1 in 30	1 in 230
African / African American	~21k	1 in 34	1 in 260
East Asian	~20k	1 in 38	1 in 230
Ashkenazi Jewish	~13k	1 in 130	1 in 420
Middle Eastern	~2,884	1 in 31	≈ 1 in 700

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): 26 of 31 coding exons well covered in gnomAD exomes; exons 3, 8, 9, 18, 19 marginal. Genomes: 30 of 31 (exon 19 below).? see exons ↓