# NM_001005361.3(DNM2):c.1135T>G (p.Phe379Val)

https://sugi.bio/variant/dnm2-p-phe379val

## Summary

**DNM2 p.Phe379Val (c.1135T>G)** is classified **Conflicting classifications of pathogenicity** in DNM2 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2016-01-06). AlphaMissense: ambiguous (0.4898); Absent from gnomAD v4.1; Associated with fetal akinesia-cerebral and retinal hemorrhage syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: No assertion criteria · rsID rs397514735 · 2 submitters · 2 linked conditions · AlphaMissense ambiguous · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DNM2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to fetal akinesia-cerebral and retinal hemorrhage syndrome.

*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 recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | DNM2 is a diagnostic-grade gene on 16 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017553/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DNM2](https://sugi.bio/atlas/gene/DNM2/) |
| Protein change (HGVS p.) | p.Phe379Val |
| Coding change (HGVS c.) | c.1135T>G |
| MANE Select transcript | [NM_001005361](https://www.ncbi.nlm.nih.gov/nuccore/NM_001005361) |
| dbSNP | [rs397514735](https://www.ncbi.nlm.nih.gov/snp/rs397514735/) |
| Variant type | single nucleotide variant |
| Location | chr19:10795378-10795378 (GRCh38) |
| ClinVar | [VCV60688](https://www.ncbi.nlm.nih.gov/clinvar/variation/60688/) |

**All HGVS expressions:** `LRG_238:g.82300T>G`, `LRG_238t1:c.1135T>G`, `NC_000019.10:g.10795378T>G`, `NC_000019.9:g.10906054T>G`, `NG_008792.1:g.82300T>G`, `NM_001005360.2:c.1135T>G`, `NM_001005360.3:c.1135T>G`, `NM_001005361.3:c.1135T>G`, `NM_001005362.3:c.1135T>G`, `NM_001190716.2:c.1135T>G`, `NM_004945.4:c.1135T>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4898) — no call either way
- REVEL 0.47 (indeterminate)
- SaProt LLR -11.78 (damaging)
- Conservation: phyloP 6.158, GERP 1.84, phastCons 1 — highly conserved
- CADD: **PHRED 26.8**. 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 0.21** across the covering region of the MANE Select transcript (10,793,783–10,795,429), spanning 1,646 bp — the region is depleted of missense variation. Chi-square p 7e-10. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**DNM2** population constraint: LOEUF 0.239, pLI 1, missense-Z 4.8688; ClinGen dosage — haploinsufficiency 0/3, 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):

- **Charcot-Marie-Tooth disease** — Definitive (AD)
- **autosomal dominant centronuclear myopathy** — Definitive (AD)

## Protein context {#protein}

Residue **379** lies in a UniProt-annotated variant site (in lccs5; hypomorphic mutation impacting on endocytosis).

AlphaFold model confidence (whole protein): pLDDT 78.38, 41% of residues very-high.

**1 experimental structure(s)** (PDB): [2YS1](https://www.rcsb.org/structure/2YS1).

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

*Describes the biological roles of DNM2 (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:** DNM2's established molecular role includes GTPase activity.


### Pathways affected {#pathways}

DNM2 participates in **12 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [Degradation of CDH1](https://reactome.org/content/detail/R-HSA-9766229) | 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 |
| [Golgi Associated Vesicle Biogenesis](https://reactome.org/content/detail/R-HSA-432722) | curated |
| [Lysosome Vesicle Biogenesis](https://reactome.org/content/detail/R-HSA-432720) | curated |
| [MHC class II antigen presentation](https://reactome.org/content/detail/R-HSA-2132295) | curated |
| [NOSTRIN mediated eNOS trafficking](https://reactome.org/content/detail/R-HSA-203641) | 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 |
| [NGF-stimulated transcription](https://reactome.org/content/detail/R-HSA-9031628) | electronic |
| [Retrograde neurotrophin signalling](https://reactome.org/content/detail/R-HSA-177504) | electronic |

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

**Molecular function:** GTPase activity, phosphatidylinositol-4,5-bisphosphate binding, SH3 domain binding.

**Biological process:** endocytosis, receptor-mediated endocytosis, autophagy, receptor internalization, transferrin transport, protein polymerization.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2016-01-06.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Uncertain significance).

**Submission history:** 2 submissions (2013–2016); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2013-06-01 |
| Inherited Neuropathy Consortium Ii, University Of Miami | Uncertain significance | no assertion criteria provided | literature only | 2016-01-06 |

## Associated conditions {#conditions}

[fetal akinesia-cerebral and retinal hemorrhage syndrome](https://sugi.bio/atlas/disease/fetal-akinesia-cerebral-and-retinal-hemorrhage-syndrome/), [Charcot-Marie-Tooth disease dominant intermediate B](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-dominant-intermediate-b/).

**Reported phenotype names (ClinVar):** Fetal akinesia-cerebral and retinal hemorrhage syndrome, Charcot-Marie-Tooth disease dominant intermediate B, MYOPATHY, CENTRONUCLEAR, LETHAL, AUTOSOMAL RECESSIVE, Lethal congenital contracture syndrome 5, CHARCOT-MARIE-TOOTH NEUROPATHY, DOMINANT INTERMEDIATE B, Charcot-Marie-Tooth disease dominant intermediate 1, CMT DI1, Charcot-Marie-Tooth disease dominant intermediate I.

## Similar variants {#similar}

Related DNM2 variant pages (same residue, condition, or type): [DNM2 p.Ala618Thr](/variant/dnm2-p-ala618thr), [DNM2 p.Arg369Gln](/variant/dnm2-p-arg369gln), [DNM2 p.Arg369Trp](/variant/dnm2-p-arg369trp), [DNM2 p.Arg465Trp](/variant/dnm2-p-arg465trp), [DNM2 p.Arg522Cys](/variant/dnm2-p-arg522cys), [DNM2 p.Arg522His](/variant/dnm2-p-arg522his), [DNM2 p.Arg523Gly](/variant/dnm2-p-arg523gly), [DNM2 p.Asp614Asn](/variant/dnm2-p-asp614asn).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 60688). 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.*