# NM_203486.3(DLL3):c.1339_1340insT (p.His447fs)

https://sugi.bio/variant/dll3-p-his447fs

## Summary

**DLL3 p.His447fs (c.1339_1340insT)** is classified **Pathogenic** in DLL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). No gnomAD frequency available for this variant; Associated with spondylocostal dysostosis 1, autosomal recessive.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2514649158 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DLL3 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to spondylocostal dysostosis 1, autosomal recessive.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010726/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DLL3](https://sugi.bio/atlas/gene/DLL3/) |
| Protein change (HGVS p.) | p.His447fs |
| Coding change (HGVS c.) | c.1339_1340insT |
| MANE Select transcript | [NM_203486](https://www.ncbi.nlm.nih.gov/nuccore/NM_203486) |
| dbSNP | [rs2514649158](https://www.ncbi.nlm.nih.gov/snp/rs2514649158/) |
| Variant type | Insertion |
| Location | chr19:39507284-39507285 (GRCh38) |
| ClinVar | [VCV1705307](https://www.ncbi.nlm.nih.gov/clinvar/variation/1705307/) |

**All HGVS expressions:** `NC_000019.10:g.39507284_39507285insT`, `NC_000019.9:g.39997924_39997925insT`, `NG_008256.1:g.13368_13369insT`, `NM_016941.4:c.1339_1340insT`, `NM_203486.3:c.1339_1340insT`

## 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 7.253, GERP -3.31, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.512, pLI 3.0199e-20. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 9**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no insertion 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}

**DLL3** population constraint: LOEUF 1.512, pLI 3.0199e-20, missense-Z -3.403. *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 **447** lies in the egf-like 6 domain; a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 65.42, 7% of residues very-high.

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

*Describes the biological roles of DLL3 (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.*


### Pathways affected {#pathways}

DLL3 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Formation of paraxial mesoderm](https://reactome.org/content/detail/R-HSA-9793380) | other |
| [Somitogenesis](https://reactome.org/content/detail/R-HSA-9824272) | other |

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

**Biological process:** skeletal system development.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-01.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2022-09-01 |

## Associated conditions {#conditions}

[spondylocostal dysostosis 1, autosomal recessive](https://sugi.bio/atlas/disease/spondylocostal-dysostosis-1-autosomal-recessive/).

**Reported phenotype names (ClinVar):** Spondylocostal dysostosis 1, autosomal recessive, DLL3-Related Spondylocostal Dysostosis, Autosomal Recessive.

## Similar variants {#similar}

Related DLL3 variant pages (same residue, condition, or type): [DLL3 c.652+1G>T](/variant/dll3-c-652-plus-1g-t), [DLL3 p.Ala317fs](/variant/dll3-p-ala317fs), [DLL3 p.Arg238Ter](/variant/dll3-p-arg238ter), [DLL3 p.Cys178Ter](/variant/dll3-p-cys178ter), [DLL3 p.Cys207fs](/variant/dll3-p-cys207fs), [DLL3 p.Cys207Ter](/variant/dll3-p-cys207ter), [DLL3 p.Cys379Tyr](/variant/dll3-p-cys379tyr), [DLL3 p.Cys464_Glu465delinsTer](/variant/dll3-p-cys464-glu465delinster).

### 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 1705307). 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.*