USP40
Chr 2ubiquitin specific peptidase 40
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.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
The highest-scoring mechanism for this gene is dominant-negative.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
285 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 35 | 0 | 35 |
Likely Pathogenic | 0 | 0 | 1 | 0 | 1 |
VUS | 1 | 181 | 11 | 0 | 193 |
Likely Benign | 0 | 11 | 0 | 1 | 12 |
Benign | 0 | 0 | 0 | 2 | 2 |
| Total | 1 | 192 | 47 | 3 | 243 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
USP40 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools