# NM_001982.4(ERBB3):c.1881_1891del (p.Asp628fs)

https://sugi.bio/variant/erbb3-p-asp628fs

## Summary

**ERBB3 p.Asp628fs (c.1881_1891del)** is classified **Likely pathogenic** in ERBB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-15). No gnomAD frequency available for this variant; Associated with ERBB3-related disorder.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2540758459 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ERBB3 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to ERBB3-related disorder.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ERBB3](https://sugi.bio/atlas/gene/ERBB3/) |
| Protein change (HGVS p.) | p.Asp628fs |
| Coding change (HGVS c.) | c.1881_1891del |
| MANE Select transcript | [NM_001982](https://www.ncbi.nlm.nih.gov/nuccore/NM_001982) |
| dbSNP | [rs2540758459](https://www.ncbi.nlm.nih.gov/snp/rs2540758459/) |
| Variant type | Deletion |
| Location | chr12:56095278-56095288 (GRCh38) |
| ClinVar | [VCV2631098](https://www.ncbi.nlm.nih.gov/clinvar/variation/2631098/) |

**All HGVS expressions:** `LRG_996:g.20171_20181del`, `LRG_996t1:c.1881_1891del`, `NC_000012.11:g.56489062_56489072del`, `NC_000012.12:g.56095278_56095288del`, `NG_011529.1:g.20171_20181del`, `NM_001982.3:c.1881_1891del11`, `NM_001982.4:c.1881_1891del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.823, GERP 1.84, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.695, pLI 2.6217e-16. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 16 of 28**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**ERBB3** population constraint: LOEUF 0.695, pLI 2.6217e-16, missense-Z 3.3038. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **628** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 72.90, 48% of residues very-high.

**23 experimental structure(s)** (PDB): [1M6B](https://www.rcsb.org/structure/1M6B), [2L9U](https://www.rcsb.org/structure/2L9U), [3KEX](https://www.rcsb.org/structure/3KEX), [3LMG](https://www.rcsb.org/structure/3LMG), [3P11](https://www.rcsb.org/structure/3P11), [4LEO](https://www.rcsb.org/structure/4LEO) — incl. mutant structure 6KBI.

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

*Describes the biological roles of ERBB3 (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:** ERBB3's established molecular role includes growth factor binding. In Reactome, ERBB3 is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**, **Signaling by ERBB2 KD Mutants**.

**Disease mechanism (Reactome):** ERBB3 loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530), [Signaling by ERBB2 KD Mutants](https://reactome.org/content/detail/R-HSA-9664565), [Signaling by ERBB2 TMD/JMD mutants](https://reactome.org/content/detail/R-HSA-9665686).

### Pathways affected {#pathways}

ERBB3 participates in **15 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | other |
| ⚕ [Signaling by ERBB2 KD Mutants](https://reactome.org/content/detail/R-HSA-9664565) | other |
| ⚕ [Signaling by ERBB2 TMD/JMD mutants](https://reactome.org/content/detail/R-HSA-9665686) | other |
| [Downregulation of ERBB2 signaling](https://reactome.org/content/detail/R-HSA-8863795) | other |
| [Downregulation of ERBB2:ERBB3 signaling](https://reactome.org/content/detail/R-HSA-1358803) | other |
| [ERBB2 Activates PTK6 Signaling](https://reactome.org/content/detail/R-HSA-8847993) | other |
| [ERBB2 Regulates Cell Motility](https://reactome.org/content/detail/R-HSA-6785631) | other |
| [GRB7 events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1306955) | other |
| [PI3K events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1963642) | other |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | other |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | other |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | other |
| [SHC1 events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1250196) | other |
| [Signaling by ERBB2](https://reactome.org/content/detail/R-HSA-1227986) | other |
| [Signaling by ERBB4](https://reactome.org/content/detail/R-HSA-1236394) | other |

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

**Molecular function:** growth factor binding, protein tyrosine kinase activator activity, ubiquitin protein ligase binding, neuregulin binding, identical protein binding, ErbB-3 class receptor binding.

**Biological process:** negative regulation of cell adhesion, signal transduction, cell surface receptor protein tyrosine kinase signaling pathway, negative regulation of signal transduction, regulation of cell population proliferation, phosphatidylinositol 3-kinase/protein kinase B signal transduction.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-15.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-09-15 |

## Associated conditions {#conditions}

[ERBB3-related disorder](https://sugi.bio/atlas/disease/erbb3-related-disorder/).

**Reported phenotype names (ClinVar):** ERBB3-related disorder, ERBB3-related condition.

## Similar variants {#similar}

Related ERBB3 variant pages (same residue, condition, or type): [ERBB3 p.Trp373Arg](/variant/erbb3-p-trp373arg), [ERBB3 c.234+2T>C](/variant/erbb3-c-234-plus-2t-c), [ERBB3 p.Arg444Ter](/variant/erbb3-p-arg444ter), [ERBB3 p.Ala913Thr](/variant/erbb3-p-ala913thr), [ERBB3 p.Gln932Pro](/variant/erbb3-p-gln932pro), [ERBB3 p.Leu1015_Glu1016insAspLeu](/variant/erbb3-p-leu1015-glu1016insaspleu), [ERBB3 p.Leu431Phe](/variant/erbb3-p-leu431phe), [ERBB3 p.Met559Ile](/variant/erbb3-p-met559ile).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2631098). 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.*