# NM_031483.7(ITCH):c.246T>C (p.Arg82=)

https://sugi.bio/variant/itch-p-arg82

## Summary

**ITCH p.Arg82= (c.246T>C)** is classified **Benign** in ITCH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). Common (popmax 10.1%, eas) — too common for a highly-penetrant pathogenic allele; Associated with syndromic multisystem autoimmune disease due to ITCH deficiency.

**At a glance:** Benign · review: Multiple submitters · rsID rs3761146 · 3 submitters · 1 linked condition · common (popmax 10.1%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the ITCH gene that is classified as benign — not considered disease-causing, submitted by 3 submitters, and is linked to syndromic multisystem autoimmune disease due to ITCH deficiency.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | ITCH is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Syndromic multisystem autoimmune disease due to Itch deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Global developmental delay — Very frequent (99-80%)
- Hepatosplenomegaly — Very frequent (99-80%)
- Failure to thrive in infancy — Very frequent (99-80%)
- Abnormal facial shape — Very frequent (99-80%)
- Relative macrocephaly — Very frequent (99-80%)
- Chronic lung disease — Very frequent (99-80%)
- Proptosis — Frequent (79-30%)
- Hypothyroidism — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010775/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ITCH](https://sugi.bio/atlas/gene/ITCH/) |
| Protein change (HGVS p.) | p.Arg82= |
| Coding change (HGVS c.) | c.246T>C |
| MANE Select transcript | [NM_031483](https://www.ncbi.nlm.nih.gov/nuccore/NM_031483) |
| dbSNP | [rs3761146](https://www.ncbi.nlm.nih.gov/snp/rs3761146/) |
| Variant type | single nucleotide variant |
| Location | chr20:34412548-34412548 (GRCh38) |
| ClinVar | [VCV538759](https://www.ncbi.nlm.nih.gov/clinvar/variation/538759/) |

**All HGVS expressions:** `LRG_354:g.54293T>C`, `NC_000020.10:g.33000354T>C`, `NC_000020.11:g.34412548T>C`, `NG_023206.1:g.54293T>C`, `NM_001257137.3:c.246T>C`, `NM_001257138.3:c.-85T>C`, `NM_001324197.2:c.246T>C`, `NM_001324198.2:c.246T>C`, `NM_031483.7:c.246T>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 10.1%, eas) — too common for a highly-penetrant pathogenic allele.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.282, GERP -2.33, phastCons 0.997 — weakly conserved position
- CADD: **PHRED 9.048**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **10.1%** (eas) · FAF95 9.88% · FAF99 9.78% · 4,528/44,722 in the highest group · 5,534/1,604,096 alleles overall — common (popmax 10.1%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 10.1% | 10 |
| Remaining individuals (not grpmax-eligible) | 0.648% | 154 |
| South Asian | 0.243% | 411 |
| Finnish (not grpmax-eligible) | 0.0813% | 1,231 |
| Admixed American | 0.075% | 1,334 |
| African / African-American | 0.0267% | 3,740 |
| European (non-Finnish) | 0.0225% | 4,436 |
| Middle Eastern | 0.0165% | 6,044 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ITCH** population constraint: LOEUF 0.343, pLI 1, missense-Z 4.361; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **syndromic multisystem autoimmune disease due to ITCH deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **82** lies in the c2 domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 76.39, 38% of residues very-high.

**12 experimental structure(s)** (PDB): [2DMV](https://www.rcsb.org/structure/2DMV), [2KYK](https://www.rcsb.org/structure/2KYK), [2NQ3](https://www.rcsb.org/structure/2NQ3), [2P4R](https://www.rcsb.org/structure/2P4R), [2YSF](https://www.rcsb.org/structure/2YSF), [3TUG](https://www.rcsb.org/structure/3TUG) — incl. mutant structure 5C7M.

## What this gene does {#gene-function}

*Describes the biological roles of ITCH (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ITCH's established molecular role includes ubiquitin-protein transferase activity. p.Arg82= falls in the c2 domain. In Reactome, ITCH is annotated in disease pathway(s) including **SARS-CoV-1 activates/modulates innate immune responses**.

**Disease mechanism (Reactome):** ITCH loss or alteration is curated in [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916).

### Pathways affected {#pathways}

ITCH participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916) | curated |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | curated |
| [Degradation of GLI1 by the proteasome](https://reactome.org/content/detail/R-HSA-5610780) | curated |
| [Downregulation of ERBB4 signaling](https://reactome.org/content/detail/R-HSA-1253288) | curated |
| [Hedgehog 'on' state](https://reactome.org/content/detail/R-HSA-5632684) | curated |
| [NOD1/2 Signaling Pathway](https://reactome.org/content/detail/R-HSA-168638) | curated |
| [Negative regulators of DDX58/IFIH1 signaling](https://reactome.org/content/detail/R-HSA-936440) | curated |
| [RUNX1 regulates transcription of genes involved in differentiation of HSCs](https://reactome.org/content/detail/R-HSA-8939236) | curated |
| [Regulation of necroptotic cell death](https://reactome.org/content/detail/R-HSA-5675482) | curated |
| [Activated NOTCH1 Transmits Signal to the Nucleus](https://reactome.org/content/detail/R-HSA-2122948) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** ubiquitin-protein transferase activity, ubiquitin-ubiquitin ligase activity, ribonucleoprotein complex binding, ubiquitin-like protein ligase binding, CXCR chemokine receptor binding, ubiquitin protein ligase activity.

**Biological process:** ubiquitin-dependent protein catabolic process, protein monoubiquitination, protein ubiquitination, receptor internalization, protein K29-linked ubiquitination, negative regulation of cytoplasmic pattern recognition receptor signaling pathway.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-02.

**Submitter consensus:** unanimous (3/3 Benign).

**Submission history:** 3 submissions (2022–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-09-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-02 |

## Associated conditions {#conditions}

[syndromic multisystem autoimmune disease due to ITCH deficiency](https://sugi.bio/atlas/disease/syndromic-multisystem-autoimmune-disease-due-to-itch-deficiency/).

**Reported phenotype names (ClinVar):** Syndromic multisystem autoimmune disease due to ITCH deficiency, not provided, not specified, AllHighlyPenetrant, AUTOIMMUNE DISEASE, MULTISYSTEM, WITH FACIAL DYSMORPHISM, none provided.

## Similar variants {#similar}

Related ITCH variant pages (same residue, condition, or type): [ITCH p.Arg82Gly](/variant/itch-p-arg82gly), [ITCH p.Arg82His](/variant/itch-p-arg82his), [ITCH p.Arg82Cys](/variant/itch-p-arg82cys), [ITCH c.1952+6T>C](/variant/itch-c-1952-plus-6t-c), [ITCH p.Arg192Ser](/variant/itch-p-arg192ser), [ITCH p.Arg217Gln](/variant/itch-p-arg217gln), [ITCH p.Arg224Cys](/variant/itch-p-arg224cys), [ITCH p.Arg763Ser](/variant/itch-p-arg763ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 538759). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*