# NM_004408.4(DNM1):c.2420C>G (p.Ser807Cys)

https://sugi.bio/variant/dnm1-p-ser807cys

## Summary

**DNM1 p.Ser807Cys (c.2420C>G)** is classified **Benign/Likely benign** in DNM1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-17). AlphaMissense: likely benign (0.1747); Ultra-rare (popmax 0.0691%, nfe); Associated with developmental and epileptic encephalopathy, 31A.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs935756107 · 5 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0691%, nfe)

## For patients & families {#patients}

This is a change in the DNM1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 submitters, 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.Ser807Cys |
| Coding change (HGVS c.) | c.2420C>G |
| MANE Select transcript | [NM_004408](https://www.ncbi.nlm.nih.gov/nuccore/NM_004408) |
| dbSNP | [rs935756107](https://www.ncbi.nlm.nih.gov/snp/rs935756107/) |
| Variant type | single nucleotide variant |
| Location | chr9:128250826-128250826 (GRCh38) |
| ClinVar | [VCV387422](https://www.ncbi.nlm.nih.gov/clinvar/variation/387422/) |

**All HGVS expressions:** `NC_000009.11:g.131013105C>G`, `NC_000009.12:g.128250826C>G`, `NG_029726.1:g.52443C>G`, `NM_001005336.3:c.2420C>G`, `NM_001288737.2:c.2420C>G`, `NM_001288738.2:c.2420C>G`, `NM_001288739.2:c.2420C>G`, `NM_004408.4:c.2420C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1747)
- REVEL 0.113 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -10.839 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- Conservation: phyloP 7.516, GERP 3.98, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.5**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.57** across the covering region of the MANE Select transcript (128,250,121–128,250,927), spanning 806 bp. Chi-square p 1.8e-10. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.50 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0691%** (nfe) · FAF95 0.0649% · FAF99 0.0632% · 724/1,047,630 in the highest group · 786/1,324,334 alleles overall — ultra-rare (popmax 0.0691%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.106% | 947 |
| European (non-Finnish) (grpmax) | 0.0691% | 1,447 |
| African / African-American | 0.00924% | 10,817 |
| Admixed American | 0.00827% | 12,098 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0052% | 19,240 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **807** 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.Ser807Cys 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-17.

**Submitter consensus:** conflicting (4 Likely benign, 1 Benign).

**Submission history:** 5 submissions (2019–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-05-06 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-08-14 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-08-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-17 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-01 |

## 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, not provided, Inborn genetic diseases, DNM1-related disorder, Epileptic encephalopathy, early infantile, 31, Developmental and epileptic encephalopathy, 31, DNM1-related condition, none provided.

## Similar variants {#similar}

Related DNM1 variant pages (same residue, condition, or type): [DNM1 c.1335+1638G>A](/variant/dnm1-c-1335-plus-1638g-a), [DNM1 p.Arg237Trp](/variant/dnm1-p-arg237trp), [DNM1 p.Arg361Gly](/variant/dnm1-p-arg361gly), [DNM1 p.Arg399Ter](/variant/dnm1-p-arg399ter), [DNM1 p.Asp211Val](/variant/dnm1-p-asp211val), [DNM1 p.Gln148Arg](/variant/dnm1-p-gln148arg), [DNM1 p.Gln148Lys](/variant/dnm1-p-gln148lys), [DNM1 p.Gly139Val](/variant/dnm1-p-gly139val).

### 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 387422). 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.*