# NM_001343.4(DAB2):c.1194del (p.Phe398fs)

https://sugi.bio/variant/dab2-p-phe398fs

## Summary

**DAB2 p.Phe398fs (c.1194del)** is classified **Uncertain significance** in DAB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-01). No gnomAD frequency available for this variant.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2479235579 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DAB2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [DAB2](https://sugi.bio/atlas/gene/DAB2/) |
| Protein change (HGVS p.) | p.Phe398fs |
| Coding change (HGVS c.) | c.1194del |
| MANE Select transcript | [NM_001343](https://www.ncbi.nlm.nih.gov/nuccore/NM_001343) |
| dbSNP | [rs2479235579](https://www.ncbi.nlm.nih.gov/snp/rs2479235579/) |
| Variant type | Deletion |
| Location | chr5:39382765-39382765 (GRCh38) |
| ClinVar | [VCV2655445](https://www.ncbi.nlm.nih.gov/clinvar/variation/2655445/) |

**All HGVS expressions:** `NC_000005.10:g.39382768del`, `NC_000005.9:g.39382870del`, `NG_030312.1:g.47469del`, `NG_083685.1:g.658del`, `NM_001244871.2:c.1131del`, `NM_001343.4:c.1194del`

## 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 4.071, GERP 2.47, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.479, pLI 0.99346), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 10 of 15**, 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}

**DAB2** population constraint: LOEUF 0.479, pLI 0.99346, missense-Z 1.4104. *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 **398** lies in the 'required for localization to clathrin-coated pits' region; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 54.33, 19% of residues very-high.

**3 experimental structure(s)** (PDB): [2LSW](https://www.rcsb.org/structure/2LSW), [6O5O](https://www.rcsb.org/structure/6O5O), [6OVF](https://www.rcsb.org/structure/6OVF).

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

*Describes the biological roles of DAB2 (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:** DAB2's established molecular role includes clathrin-cargo adaptor activity. p.Phe398fs falls in the required for localization to clathrin-coated pits region.


### Pathways affected {#pathways}

DAB2 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cargo recognition for clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856825) | curated |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [Formation of annular gap junctions](https://reactome.org/content/detail/R-HSA-196025) | curated |
| [Gap junction degradation](https://reactome.org/content/detail/R-HSA-190873) | curated |

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

**Molecular function:** clathrin-cargo adaptor activity, cargo receptor activity, SMAD binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, transforming growth factor beta receptor signaling pathway, positive regulation of epithelial to mesenchymal transition, positive regulation of cell migration, positive regulation of proteasomal ubiquitin-dependent protein catabolic process, leading edge cell differentiation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-01.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-10-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

### 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 2655445). 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.*