# NM_003183.6(ADAM17):c.1443G>A (p.Ser481=)

https://sugi.bio/variant/adam17-p-ser481

## Summary

**ADAM17 p.Ser481= (c.1443G>A)** is classified **Likely benign** in ADAM17 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-10). Very rare (popmax 0.00167%, amr); Associated with inflammatory skin and bowel disease, neonatal, 1.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the ADAM17 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to inflammatory skin and bowel disease, neonatal, 1.

*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 | ADAM17 is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Neonatal erythroderma-autoinflammation-inflammatory bowel disease syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Blepharitis — Frequent (79-30%)
- Onychogryposis — Frequent (79-30%)
- Psoriasiform dermatitis — Frequent (79-30%)
- Recurrent bacterial skin infections — Frequent (79-30%)
- Chronic monilial nail infection — Frequent (79-30%)
- Erythema — Frequent (79-30%)
- Perianal rash — Frequent (79-30%)
- Horizontal eyebrow — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018429/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ADAM17](https://sugi.bio/atlas/gene/ADAM17/) |
| Protein change (HGVS p.) | p.Ser481= |
| Coding change (HGVS c.) | c.1443G>A |
| MANE Select transcript | [NM_003183](https://www.ncbi.nlm.nih.gov/nuccore/NM_003183) |
| Variant type | single nucleotide variant |
| Location | chr2:9505267-9505267 (GRCh38) |
| ClinVar | [VCV4693713](https://www.ncbi.nlm.nih.gov/clinvar/variation/4693713/) |

**All HGVS expressions:** `LRG_1203:g.55522G>A`, `LRG_1203t1:c.1443G>A`, `NC_000002.11:g.9645396C>T`, `NC_000002.12:g.9505267C>T`, `NG_029873.1:g.55522G>A`, `NM_001382777.1:c.783G>A`, `NM_001382778.1:c.546G>A`, `NM_003183.6:c.1443G>A`

## 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 1.035, GERP 0.34, phastCons 0.998 — weakly conserved position
- CADD: **PHRED 11.22**. 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 (C>A, Δ0.24 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 (gnomAD v4.1): grpmax **0.00167%** (amr) · FAF95 0.000247% · FAF99 0.000159% · 1/60,008 in the highest group · 10/1,614,052 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 60,008 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,484 |
| African / African-American | 0.00133% | 74,910 |
| European (non-Finnish) | 0.000593% | 168,578 |

*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}

**ADAM17** population constraint: LOEUF 0.565, pLI 0.10138, missense-Z 2.5759. *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):

- **congenital heart disease** — Limited (AD)
- **inflammatory skin and bowel disease, neonatal, 1** — Definitive (AR)

## Protein context {#protein}

Residue **481** lies in a β-strand; the disintegrin domain.

AlphaFold model confidence (whole protein): pLDDT 72.72, 25% of residues very-high.

**33 experimental structure(s)** (PDB): [1BKC](https://www.rcsb.org/structure/1BKC), [1ZXC](https://www.rcsb.org/structure/1ZXC), [2A8H](https://www.rcsb.org/structure/2A8H), [2DDF](https://www.rcsb.org/structure/2DDF), [2FV5](https://www.rcsb.org/structure/2FV5), [2FV9](https://www.rcsb.org/structure/2FV9).

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

*Describes the biological roles of ADAM17 (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:** ADAM17's established molecular role includes endopeptidase activity. p.Ser481= falls in the disintegrin domain. In Reactome, ADAM17 is annotated in disease pathway(s) including **CD163 mediating an anti-inflammatory response**, **Constitutive Signaling by NOTCH1 HD Domain Mutants**.

**Disease mechanism (Reactome):** ADAM17 loss or alteration is curated in [CD163 mediating an anti-inflammatory response](https://reactome.org/content/detail/R-HSA-9662834), [Constitutive Signaling by NOTCH1 HD Domain Mutants](https://reactome.org/content/detail/R-HSA-2691232), [Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2894862).

### Pathways affected {#pathways}

ADAM17 participates in **13 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [CD163 mediating an anti-inflammatory response](https://reactome.org/content/detail/R-HSA-9662834) | curated |
| ⚕ [Constitutive Signaling by NOTCH1 HD Domain Mutants](https://reactome.org/content/detail/R-HSA-2691232) | curated |
| ⚕ [Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2894862) | curated |
| ⚕ [Constitutive Signaling by NOTCH1 PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2644606) | curated |
| ⚕ [Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant](https://reactome.org/content/detail/R-HSA-2660826) | curated |
| [Regulated proteolysis of p75NTR](https://reactome.org/content/detail/R-HSA-193692) | curated |
| [TNF signaling](https://reactome.org/content/detail/R-HSA-75893) | curated |
| [Activated NOTCH1 Transmits Signal to the Nucleus](https://reactome.org/content/detail/R-HSA-2122948) | electronic |
| [Collagen degradation](https://reactome.org/content/detail/R-HSA-1442490) | electronic |
| [Growth hormone receptor signaling](https://reactome.org/content/detail/R-HSA-982772) | electronic |
| [Nuclear signaling by ERBB4](https://reactome.org/content/detail/R-HSA-1251985) | electronic |
| [Release of Hh-Np from the secreting cell](https://reactome.org/content/detail/R-HSA-5362798) | electronic |
| [Signaling by EGFR](https://reactome.org/content/detail/R-HSA-177929) | electronic |

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

**Molecular function:** endopeptidase activity, metalloendopeptidase activity, Notch binding, interleukin-6 receptor binding, integrin binding, metallopeptidase activity.

**Biological process:** response to hypoxia, proteolysis, membrane protein ectodomain proteolysis, cell adhesion, epidermal growth factor receptor signaling pathway, Notch receptor processing.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-10.

**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 | 2025-12-10 |

## Associated conditions {#conditions}

[inflammatory skin and bowel disease, neonatal, 1](https://sugi.bio/atlas/disease/inflammatory-skin-and-bowel-disease-neonatal-1/).

**Reported phenotype names (ClinVar):** Inflammatory skin and bowel disease, neonatal, 1.

## Similar variants {#similar}

Related ADAM17 variant pages (same residue, condition, or type): [ADAM17 p.Ser481Leu](/variant/adam17-p-ser481leu), [ADAM17 p.Arg651Ter](/variant/adam17-p-arg651ter), [ADAM17 p.Ala742Thr](/variant/adam17-p-ala742thr), [ADAM17 p.Ala806Pro](/variant/adam17-p-ala806pro), [ADAM17 p.Ala806Ser](/variant/adam17-p-ala806ser), [ADAM17 p.Arg132Lys](/variant/adam17-p-arg132lys), [ADAM17 p.Arg177His](/variant/adam17-p-arg177his), [ADAM17 p.Arg738Cys](/variant/adam17-p-arg738cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 4693713). 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.*