ITCH
Chr 20itchy E3 ubiquitin protein ligase
Also known as: ADMFD, AIF4, AIP4, NAPP1
ITCH encodes a HECT domain E3 ubiquitin ligase that transfers ubiquitin to protein substrates for degradation and plays an essential role in regulating inflammatory signaling pathways and immune responses. Biallelic mutations cause autosomal recessive syndromic multisystem autoimmune disease with facial dysmorphism. The gene is highly constrained against loss-of-function variants (pLI 0.999, LOEUF 0.218), reflecting its critical role in immune system regulation.
Definitive — sufficient evidence for diagnostic panels
Some data sources returned errors (1)
omim: Error: OMIM fetch failed: 429
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Highly missense-constrained (top ~0.1%)
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
500 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 | 11 | 0 | 9 | 0 | 20 |
Likely Pathogenic | 5 | 1 | 4 | 0 | 10 |
VUS | 2 | 146 | 11 | 4 | 163 |
Likely Benign | 0 | 5 | 129 | 117 | 251 |
Benign | 0 | 0 | 14 | 0 | 14 |
Conflicting | — | 6 | |||
| Total | 18 | 152 | 167 | 121 | 464 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
ITCH · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
CongenItal Naevus Cohort for Longitudinal Evaluation
RECRUITINGThe Skin Microbiome in Graft Versus Host Disease
ACTIVE NOT RECRUITINGDefining the Skin and Blood Biomarkers of Pediatric Atopic Dermatitis
ACTIVE NOT RECRUITINGLong-Term Follow-Up in Women With Early Breast Cancer Three Years of More Post Primary Treatment
ACTIVE NOT RECRUITINGVaginal CO2 Laser Therapy for Genitourinary Syndrome in Breast Cancer Survivors
RECRUITINGClinical and Molecular Study to Evaluate the Effect of the Pixel CO2 Laser (FemiLiftTM) for the Treatment of Vulvo-Vaginal Atrophy
RECRUITINGMother-Infant Cohort Study in Malaysia and China
RECRUITINGStudy of the Preventive Effects and Mechanisms of Yeast β-Glucan on Upper Respiratory Tract Infections
NOT YET RECRUITINGPathophysiological Study of the Sensitive Scalp
RECRUITINGA Study to Assess the Efficacy and Safety of PG-011 Gel in Adolescents and Adults With Atopic Dermatitis
RECRUITINGIdentification of the Mechanism of Non-histaminergic Itch Inducing Epigenetic Changes
ACTIVE NOT RECRUITINGDrug-induced Liver Injury: Itching Study
RECRUITINGExternal Resources
Links to major genomics databases and tools