# NM_001376.5(DYNC1H1):c.5773C>T (p.Arg1925Trp)

https://sugi.bio/variant/dync1h1-p-arg1925trp

## Summary

**DYNC1H1 p.Arg1925Trp (c.5773C>T)** is classified **Uncertain significance** in DYNC1H1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-30). AlphaMissense: likely pathogenic (0.979); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs745893369 · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the DYNC1H1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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:** [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.Arg1925Trp |
| Coding change (HGVS c.) | c.5773C>T |
| MANE Select transcript | [NM_001376](https://www.ncbi.nlm.nih.gov/nuccore/NM_001376) |
| dbSNP | [rs745893369](https://www.ncbi.nlm.nih.gov/snp/rs745893369/) |
| Variant type | single nucleotide variant |
| Location | chr14:102007064-102007064 (GRCh38) |
| ClinVar | [VCV1749562](https://www.ncbi.nlm.nih.gov/clinvar/variation/1749562/) |

**All HGVS expressions:** `NC_000014.8:g.102473401C>T`, `NC_000014.9:g.102007064C>T`, `NG_008777.1:g.47537C>T`, `NM_001376.5:c.5773C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.979)
- REVEL 0.333 (indeterminate)
- Conservation: phyloP 7.614, GERP -0.948, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. 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 0.20** across the covering region of the MANE Select transcript (102,006,150–102,008,308), spanning 2,158 bp — the region is depleted of missense variation. Chi-square p 6.3e-17. 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, Δ0.77 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 **0.00167%** (amr) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/60,022 in the highest group · 3/1,461,892 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 60,022 |
| European (non-Finnish) | 0.000169% | 590,016 |

*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, triplosensitivity 0 (0–3 scale). *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 **1925** lies in the 'aaa 1' 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.Arg1925Trp falls in the aaa 1 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-06-30.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2018–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-02-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-06-30 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related DYNC1H1 variant pages (same residue, condition, or type): [DYNC1H1 p.Arg1925=](/variant/dync1h1-p-arg1925), [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).

### 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 1749562). 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.*