# NM_004408.4(DNM1):c.2375_2393del (p.Arg792fs)

https://sugi.bio/variant/dnm1-p-arg792fs

## Summary

**DNM1 p.Arg792fs (c.2375_2393del)** is classified **Uncertain significance** in DNM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-05). No gnomAD frequency available for this variant; Associated with developmental and epileptic encephalopathy, 31A.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2539127769 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DNM1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to developmental and epileptic encephalopathy, 31A.

*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 dominant, Multigenic/multifactorial, Not applicable |
| Age of onset (of this condition) | Childhood, Infancy |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DNM1 is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Lennox-Gastaut syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Intellectual disability — Very frequent (99-80%)
- Encephalopathy — Very frequent (99-80%)
- EEG with focal sharp slow waves — Very frequent (99-80%)
- Atypical behavior — Frequent (79-30%)
- Aggressive behavior — Frequent (79-30%)
- Autistic behavior — Frequent (79-30%)
- Irritability — Frequent (79-30%)
- Hyperactivity — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016094/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DNM1](https://sugi.bio/atlas/gene/DNM1/) |
| Protein change (HGVS p.) | p.Arg792fs |
| Coding change (HGVS c.) | c.2375_2393del |
| MANE Select transcript | [NM_004408](https://www.ncbi.nlm.nih.gov/nuccore/NM_004408) |
| dbSNP | [rs2539127769](https://www.ncbi.nlm.nih.gov/snp/rs2539127769/) |
| Variant type | Deletion |
| Location | chr9:128250777-128250795 (GRCh38) |
| ClinVar | [VCV2826338](https://www.ncbi.nlm.nih.gov/clinvar/variation/2826338/) |

**All HGVS expressions:** `NC_000009.11:g.131013060_131013078del`, `NC_000009.12:g.128250781_128250799del`, `NG_029726.1:g.52398_52416del`, `NG_182144.1:g.585_603del`, `NG_182145.1:g.75_93del`, `NM_001005336.3:c.2375_2393del`, `NM_001288737.2:c.2375_2393del`, `NM_001288738.2:c.2375_2393del`, `NM_001288739.2:c.2375_2393del`, `NM_001374269.1:c.2375_2393del`, `NM_004408.4:c.2375_2393del`

## 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 10.921, GERP 1.82, 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 0.417, pLI 0.99997), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 21 of 22**, 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}

**DNM1** population constraint: LOEUF 0.417, pLI 0.99997, missense-Z 5.0313; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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):

- **genetic developmental and epileptic encephalopathy** — Moderate (AR)
- **genetic developmental and epileptic encephalopathy** — Definitive (AD)

## Protein context {#protein}

Residue **792** lies in a UniProt-annotated variant site (in dee31b); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 78.87, 38% of residues very-high.

**22 experimental structure(s)** (PDB): [1DYN](https://www.rcsb.org/structure/1DYN), [2DYN](https://www.rcsb.org/structure/2DYN), [2X2E](https://www.rcsb.org/structure/2X2E), [2X2F](https://www.rcsb.org/structure/2X2F), [3SNH](https://www.rcsb.org/structure/3SNH), [3ZYC](https://www.rcsb.org/structure/3ZYC).

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

*Describes the biological roles of DNM1 (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:** DNM1's established molecular role includes RNA binding. p.Arg792fs falls in the disordered region.


### Pathways affected {#pathways}

DNM1 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [EPH-ephrin mediated repulsion of cells](https://reactome.org/content/detail/R-HSA-3928665) | 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 |
| [MHC class II antigen presentation](https://reactome.org/content/detail/R-HSA-2132295) | curated |
| [Recycling pathway of L1](https://reactome.org/content/detail/R-HSA-437239) | curated |
| [Toll Like Receptor 4 (TLR4) Cascade](https://reactome.org/content/detail/R-HSA-166016) | curated |
| [Retrograde neurotrophin signalling](https://reactome.org/content/detail/R-HSA-177504) | electronic |

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

**Molecular function:** RNA binding, GTPase activity, phosphatidylinositol-4,5-bisphosphate binding, phosphatidylinositol-3,4,5-trisphosphate binding, identical protein binding, protein homodimerization activity.

**Biological process:** endocytosis, receptor-mediated endocytosis, endosome organization, protein homooligomerization, protein homotetramerization, vesicle scission.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-01-05.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-01-05 |

## Associated conditions {#conditions}

[developmental and epileptic encephalopathy, 31A](https://sugi.bio/atlas/disease/developmental-and-epileptic-encephalopathy-31a/).

**Reported phenotype names (ClinVar):** Developmental and epileptic encephalopathy, 31A, Epileptic encephalopathy, early infantile, 31, Developmental and epileptic encephalopathy, 31.

## Similar variants {#similar}

Related DNM1 variant pages (same residue, condition, or type): [DNM1 c.1493+14del](/variant/dnm1-c-1493-plus-14del), [DNM1 p.Arg256fs](/variant/dnm1-p-arg256fs), [DNM1 p.Gly139_Thr141del](/variant/dnm1-p-gly139-thr141del), [DNM1 p.Leu69fs](/variant/dnm1-p-leu69fs), [DNM1 p.Pro790fs](/variant/dnm1-p-pro790fs), [DNM1 p.Trp542fs](/variant/dnm1-p-trp542fs), [DNM1 c.1422+5del](/variant/dnm1-c-1422-plus-5del), [DNM1 c.993-13_993-11del](/variant/dnm1-c-993-minus-13-993-minus-11del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2826338). 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.*