# NM_001377.3(DYNC2H1):c.2386C>A (p.Arg796=)

https://sugi.bio/variant/dync2h1-p-arg796

## Summary

**DYNC2H1 p.Arg796= (c.2386C>A)** is classified **Conflicting classifications of pathogenicity** in DYNC2H1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-06-21). Very rare (popmax 0.00017%, nfe); Associated with asphyxiating thoracic dystrophy 3.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · 2 submitters · 1 linked condition · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the DYNC2H1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to asphyxiating thoracic dystrophy 3.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015613/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DYNC2H1](https://sugi.bio/atlas/gene/DYNC2H1/) |
| Protein change (HGVS p.) | p.Arg796= |
| Coding change (HGVS c.) | c.2386C>A |
| MANE Select transcript | [NM_001377](https://www.ncbi.nlm.nih.gov/nuccore/NM_001377) |
| Variant type | single nucleotide variant |
| Location | chr11:103135760-103135760 (GRCh38) |
| ClinVar | [VCV4530603](https://www.ncbi.nlm.nih.gov/clinvar/variation/4530603/) |

**All HGVS expressions:** `NC_000011.10:g.103135760C>A`, `NC_000011.9:g.103006489C>A`, `NG_016423.2:g.31330C>A`, `NM_001080463.2:c.2386C>A`, `NM_001377.3:c.2386C>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.29) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 7.639, GERP 2.2, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 9.198**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.29**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 40 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.25** (loss), gain 0.01 / loss 0.25. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,178,352 in the highest group · 3/1,610,878 alleles overall — very rare (popmax 0.00017%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00157% | 63,816 |
| European (non-Finnish) (grpmax) | 0.00017% | 589,175 |

Finnish 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}

**DYNC2H1** population constraint: LOEUF 0.859, pLI 1.5874e-83, missense-Z 0.47463; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/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):

- **asphyxiating thoracic dystrophy 3** — Definitive (AR)

## Protein context {#protein}

Residue **796** lies in the 'stem' region.

**4 experimental structure(s)** (PDB): [4RH7](https://www.rcsb.org/structure/4RH7), [6RLB](https://www.rcsb.org/structure/6RLB), [8RGG](https://www.rcsb.org/structure/8RGG), [8RGH](https://www.rcsb.org/structure/8RGH).

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

*Describes the biological roles of DYNC2H1 (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.*


### Pathways affected {#pathways}

DYNC2H1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Hedgehog 'off' state](https://reactome.org/content/detail/R-HSA-5610787) | curated |
| [Intraflagellar transport](https://reactome.org/content/detail/R-HSA-5620924) | curated |

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

**Biological process:** Golgi organization.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2023-06-21.

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

**Submission history:** 2 submissions (2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Functional Genomics, Research Centre for Medical Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing |  |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-06-21 |

## Associated conditions {#conditions}

[asphyxiating thoracic dystrophy 3](https://sugi.bio/atlas/disease/asphyxiating-thoracic-dystrophy-3/).

**Reported phenotype names (ClinVar):** Asphyxiating thoracic dystrophy 3, not specified, SHORT-RIB THORACIC DYSPLASIA 3 WITH OR WITHOUT POLYDACTYLY, POLYDACTYLY WITH NEONATAL CHONDRODYSTROPHY, TYPE I, SHORT-RIB THORACIC DYSPLASIA 3/6 WITH POLYDACTYLY, DIGENIC, Short rib polydactyly syndrome 2B, Saldino-Noonan Syndrome, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **796** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DYNC2H1 p.Arg796fs](/variant/dync2h1-p-arg796fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DYNC2H1 variant pages (same residue, condition, or type): [DYNC2H1 p.Arg796Trp](/variant/dync2h1-p-arg796trp), [DYNC2H1 p.Arg796Leu](/variant/dync2h1-p-arg796leu), [DYNC2H1 p.Arg796Gln](/variant/dync2h1-p-arg796gln), [DYNC2H1 c.10042+2T>G](/variant/dync2h1-c-10042-plus-2t-g), [DYNC2H1 c.10462-2A>G](/variant/dync2h1-c-10462-minus-2a-g), [DYNC2H1 c.10606-14A>G](/variant/dync2h1-c-10606-minus-14a-g), [DYNC2H1 c.12156+1G>A](/variant/dync2h1-c-12156-plus-1g-a), [DYNC2H1 c.12457-1G>C](/variant/dync2h1-c-12457-minus-1g-c).

### 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 4530603). 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.*