# NM_001376.5(DYNC1H1):c.1777G>T (p.Val593Phe)

https://sugi.bio/variant/dync1h1-p-val593phe

## Summary

**DYNC1H1 p.Val593Phe (c.1777G>T)** is classified **Likely pathogenic** in DYNC1H1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-10). AlphaMissense: likely pathogenic (0.8685); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease axonal type 2O.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2047932647 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DYNC1H1 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Charcot-Marie-Tooth disease axonal type 2O.

*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 |
| Age of onset (of this condition) | Childhood |
| Prevalence | <1 / 1 000 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DYNC1H1 is a diagnostic-grade gene on 15 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012434/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DYNC1H1](https://sugi.bio/atlas/gene/DYNC1H1/) |
| Protein change (HGVS p.) | p.Val593Phe |
| Coding change (HGVS c.) | c.1777G>T |
| MANE Select transcript | [NM_001376](https://www.ncbi.nlm.nih.gov/nuccore/NM_001376) |
| dbSNP | [rs2047932647](https://www.ncbi.nlm.nih.gov/snp/rs2047932647/) |
| Variant type | single nucleotide variant |
| Location | chr14:101986002-101986002 (GRCh38) |
| ClinVar | [VCV943318](https://www.ncbi.nlm.nih.gov/clinvar/variation/943318/) |

**All HGVS expressions:** `NC_000014.8:g.102452339G>T`, `NC_000014.9:g.101986002G>T`, `NG_008777.1:g.26475G>T`, `NM_001376.5:c.1777G>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.8685) — concordant with the pathogenic call
- REVEL 0.292 (indeterminate)
- Conservation: phyloP 11.847, GERP 2.4, phastCons 1 — highly conserved (agrees)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- CADD: **PHRED 23.1**. 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 0.43** across the covering region of the MANE Select transcript (101,983,019–101,986,621), spanning 3,602 bp. Chi-square p 2.9e-46. 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}

**DYNC1H1** population constraint: LOEUF 0.117, pLI 1, missense-Z 16.078; 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):

- **distal hereditary motor neuropathy** — Definitive (AD)

## Protein context {#protein}

Residue **593** lies in the 'stem' region; the 'interaction with dync1i2' region.

**98 experimental structure(s)** (PDB): [30DR](https://www.rcsb.org/structure/30DR), [5NUG](https://www.rcsb.org/structure/5NUG), [5OWO](https://www.rcsb.org/structure/5OWO), [6F1T](https://www.rcsb.org/structure/6F1T), [6F1U](https://www.rcsb.org/structure/6F1U), [6F1V](https://www.rcsb.org/structure/6F1V) — incl. mutant structure 9BN3.

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

*Describes the biological roles of DYNC1H1 (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:** DYNC1H1's established molecular role includes RNA binding. p.Val593Phe falls in the stem region. In Reactome, DYNC1H1 is annotated in disease pathway(s) including **HCMV Early Events**.

**Disease mechanism (Reactome):** DYNC1H1 loss or alteration is curated in [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690).

### Pathways affected {#pathways}

DYNC1H1 participates in **21 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690) | curated |
| [AURKA Activation by TPX2](https://reactome.org/content/detail/R-HSA-8854518) | curated |
| [Amplification  of signal from unattached  kinetochores via a MAD2  inhibitory signal](https://reactome.org/content/detail/R-HSA-141444) | curated |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |
| [COPI-independent Golgi-to-ER retrograde traffic](https://reactome.org/content/detail/R-HSA-6811436) | curated |
| [COPI-mediated anterograde transport](https://reactome.org/content/detail/R-HSA-6807878) | curated |
| [EML4 and NUDC in mitotic spindle formation](https://reactome.org/content/detail/R-HSA-9648025) | curated |
| [HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand](https://reactome.org/content/detail/R-HSA-3371497) | curated |
| [Loss of Nlp from mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380259) | curated |
| [Loss of proteins required for interphase microtubule organization from the centrosome](https://reactome.org/content/detail/R-HSA-380284) | curated |
| [MHC class II antigen presentation](https://reactome.org/content/detail/R-HSA-2132295) | curated |
| [Mitotic Prometaphase](https://reactome.org/content/detail/R-HSA-68877) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Processing of antigen in germinal center B cells](https://reactome.org/content/detail/R-HSA-9979719) | curated |
| [RHO GTPases Activate Formins](https://reactome.org/content/detail/R-HSA-5663220) | curated |
| [Recruitment of NuMA to mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380320) | curated |
| [Recruitment of mitotic centrosome proteins and complexes](https://reactome.org/content/detail/R-HSA-380270) | curated |
| [Regulation of PLK1 Activity at G2/M Transition](https://reactome.org/content/detail/R-HSA-2565942) | curated |
| [Resolution of Sister Chromatid Cohesion](https://reactome.org/content/detail/R-HSA-2500257) | curated |
| [Separation of Sister Chromatids](https://reactome.org/content/detail/R-HSA-2467813) | curated |
| [Aggrephagy](https://reactome.org/content/detail/R-HSA-9646399) | electronic |

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

**Molecular function:** RNA binding, identical protein binding, dynein light intermediate chain binding.

**Biological process:** positive regulation of intracellular transport, establishment of spindle localization, regulation of mitotic spindle organization, regulation of metaphase plate congression, positive regulation of spindle assembly.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-06-10 |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease axonal type 2O](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-axonal-type-2o/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease axonal type 2O, CHARCOT-MARIE-TOOTH NEUROPATHY, AXONAL, TYPE 2O, CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2O, Charcot-Marie-Tooth Neuropathy Type 2O, Charcot-Marie-Tooth disease, axonal, type 20.

## Similar variants {#similar}

Related DYNC1H1 variant pages (same residue, condition, or type): [DYNC1H1 p.Arg1567Gln](/variant/dync1h1-p-arg1567gln), [DYNC1H1 p.Arg1623Gln](/variant/dync1h1-p-arg1623gln), [DYNC1H1 p.Arg1962Cys](/variant/dync1h1-p-arg1962cys), [DYNC1H1 p.Arg1962His](/variant/dync1h1-p-arg1962his), [DYNC1H1 p.Arg2332Cys](/variant/dync1h1-p-arg2332cys), [DYNC1H1 p.Arg251Ser](/variant/dync1h1-p-arg251ser), [DYNC1H1 p.Arg264Leu](/variant/dync1h1-p-arg264leu), [DYNC1H1 p.Arg292Trp](/variant/dync1h1-p-arg292trp).

### 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 943318). 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.*