ITCH
Chr 20ARitchy E3 ubiquitin protein ligase
Also known as: ADMFD, AIF4, AIP4, NAPP1
This gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, thus targeting specific proteins for lysosomal degradation. The encoded protein plays a role in multiple cellular processes including erythroid and lymphoid cell differentiation and the regulation of immune responses. Mutations in this gene are a cause of syndromic multisystem autoimmune disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Highly missense-constrained (top ~0.1%)
This gene — mechanism propensity
Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.
The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
557 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 | 13 | 0 | 4 | 0 | 17 |
Likely Pathogenic | 6 | 1 | 1 | 0 | 8 |
VUS | 2 | 178 | 14 | 4 | 198 |
Likely Benign | 0 | 6 | 133 | 135 | 274 |
Benign | 0 | 0 | 15 | 2 | 17 |
Conflicting | — | 7 | |||
| Total | 21 | 185 | 167 | 141 | 521 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →16 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap ITCH — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →
Protein Context — Lollipop Plot
ITCH · 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
European Cystinosis Cohort
RECRUITINGRCT Comparing Intravaginal Laser Therapy to Sham in Post-menopausal Women with Recurrent Urinary Tract Infections
ACTIVE NOT RECRUITINGEx Vivo Gene Therapy Clinical Trial for RDEB Using Genetically Corrected Autologous Skin Equivalent Grafts
ACTIVE NOT RECRUITINGCD4^LVFOXP3 in Participants With IPEX
RECRUITINGA Phase I Clinical Trial to Evaluate the Single Dose Ascending and Food Effects of PG-033 in Healthy Adults
RECRUITINGClinical and Molecular Study to Evaluate the Effect of the Pixel CO2 Laser (FemiLiftTM) for the Treatment of Vulvo-Vaginal Atrophy
RECRUITINGPosterior Nasal Nerve Combined with Anterior Ethmoid Neurotomy for Idiopathic Rhinitis
RECRUITINGPhase IIa Study on Flonoltinib Maleate Tablets in the Treatment of Patients With Polycythemia Vera
RECRUITINGA Phase 3 Study of Pacritinib in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis
ACTIVE NOT RECRUITINGMind and Skin - the Neurocutaneous Axis in Atopic Eczema
RECRUITINGAkkermansia Probiotics Plus Anti-PD-1 Monoclonal Antibody in MSS/pMMR Advanced Colorectal Cancer
ACTIVE NOT RECRUITINGDrug-induced Liver Injury: Itching Study
RECRUITINGExternal Resources
Links to major genomics databases and tools