# NM_031483.7(ITCH):c.609A>C (p.Ser203=)

https://sugi.bio/variant/itch-p-ser203

## Summary

**ITCH p.Ser203= (c.609A>C)** is classified **Likely benign** in ITCH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-20). Absent from gnomAD v4.1; Associated with syndromic multisystem autoimmune disease due to ITCH deficiency.

**At a glance:** Likely benign · review: Single submitter · rsID rs2146279814 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ITCH gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, 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.Ser203= |
| Coding change (HGVS c.) | c.609A>C |
| MANE Select transcript | [NM_031483](https://www.ncbi.nlm.nih.gov/nuccore/NM_031483) |
| dbSNP | [rs2146279814](https://www.ncbi.nlm.nih.gov/snp/rs2146279814/) |
| Variant type | single nucleotide variant |
| Location | chr20:34438561-34438561 (GRCh38) |
| ClinVar | [VCV1668199](https://www.ncbi.nlm.nih.gov/clinvar/variation/1668199/) |

**All HGVS expressions:** `LRG_354:g.80305A>C`, `NC_000020.10:g.33026366A>C`, `NC_000020.11:g.34438561A>C`, `NG_023206.1:g.80305A>C`, `NM_001257137.3:c.732A>C`, `NM_001257138.3:c.279A>C`, `NM_001324197.2:c.732A>C`, `NM_001324198.2:c.609A>C`, `NM_031483.7:c.609A>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 4.553, GERP 0.289, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 11.12**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.38 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **203** lies in the 'disordered' region.

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.Ser203= falls in the disordered region. 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-20.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-06-20 |

## 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, AUTOIMMUNE DISEASE, MULTISYSTEM, WITH FACIAL DYSMORPHISM.

## Similar variants {#similar}

Related ITCH variant pages (same residue, condition, or type): [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), [ITCH p.Arg82Gly](/variant/itch-p-arg82gly), [ITCH p.Arg82His](/variant/itch-p-arg82his), [ITCH p.Asn110Ser](/variant/itch-p-asn110ser).

### 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 1668199). 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.*