# NM_001079520.2(DACT1):c.1362_1363del (p.Ser454fs)

https://sugi.bio/variant/dact1-p-ser454fs

## Summary

**DACT1 p.Ser454fs (c.1362_1363del)** is classified **Likely pathogenic** in DACT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-17). No gnomAD frequency available for this variant.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2140219280 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DACT1 gene that is considered likely disease-causing, 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 | [DACT1](https://sugi.bio/atlas/gene/DACT1/) |
| Protein change (HGVS p.) | p.Ser454fs |
| Coding change (HGVS c.) | c.1362_1363del |
| MANE Select transcript | [NM_001079520](https://www.ncbi.nlm.nih.gov/nuccore/NM_001079520) |
| dbSNP | [rs2140219280](https://www.ncbi.nlm.nih.gov/snp/rs2140219280/) |
| Variant type | Deletion |
| Location | chr14:58646096-58646097 (GRCh38) |
| ClinVar | [VCV1184920](https://www.ncbi.nlm.nih.gov/clinvar/variation/1184920/) |

**All HGVS expressions:** `NC_000014.8:g.59112814_59112815del`, `NC_000014.9:g.58646096_58646097del`, `NG_032025.1:g.17029_17030del`, `NM_001079520.2:c.1362_1363del`, `NM_016651.6:c.1473_1474del`, `NR_046093.2:n.1142_1143del`, `NR_046095.1:n.1443_1444del`, `NR_165650.1:n.1253_1254del`, `NR_165651.1:n.1522_1523del`, `NR_165652.1:n.1554_1555del`

## 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 3.639, GERP -0.368, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.703, pLI 0.16566. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (4 of 4)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- 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}

**DACT1** population constraint: LOEUF 0.703, pLI 0.16566, missense-Z -0.78096. *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 **454** lies in a UniProt-annotated variant site (in tbs2; the mutant protein is stable and expressed); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 50.95, 3% of residues very-high.

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

*Describes the biological roles of DACT1 (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:** DACT1's established molecular role includes beta-catenin binding. p.Ser454fs falls in the disordered region.


### Pathways affected {#pathways}

DACT1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Degradation of DVL](https://reactome.org/content/detail/R-HSA-4641258) | other |

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

**Molecular function:** beta-catenin binding, histone deacetylase binding, protein kinase A binding, RNA polymerase II-specific DNA-binding transcription factor binding, transcription regulator inhibitor activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, neural tube development, positive regulation of Wnt signaling pathway, negative regulation of Wnt signaling pathway, regulation of protein stability, positive regulation of protein catabolic process.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-06-17.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-06-17 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related DACT1 variant pages (same residue, condition, or type): [DACT1 p.Gln390fs](/variant/dact1-p-gln390fs).

### 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 1184920). 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.*