# NM_001377.3(DYNC2H1):c.21C>T (p.Asp7=)

https://sugi.bio/variant/dync2h1-p-asp7

## Summary

**DYNC2H1 p.Asp7= (c.21C>T)** is classified **Benign/Likely benign** in DYNC2H1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 12.6%, mid) — too common for a highly-penetrant pathogenic allele; Associated with asphyxiating thoracic dystrophy 3.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs17301028 · 8 submitters · 2 linked conditions · common (popmax 12.6%, mid) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the DYNC2H1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 8 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.Asp7= |
| Coding change (HGVS c.) | c.21C>T |
| MANE Select transcript | [NM_001377](https://www.ncbi.nlm.nih.gov/nuccore/NM_001377) |
| dbSNP | [rs17301028](https://www.ncbi.nlm.nih.gov/snp/rs17301028/) |
| Variant type | single nucleotide variant |
| Location | chr11:103109595-103109595 (GRCh38) |
| ClinVar | [VCV301995](https://www.ncbi.nlm.nih.gov/clinvar/variation/301995/) |

**All HGVS expressions:** `NC_000011.10:g.103109595C>T`, `NC_000011.9:g.102980324C>T`, `NG_016423.2:g.5165C>T`, `NM_001080463.2:c.21C>T`, `NM_001377.3:c.21C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 12.6%, mid) — too common for a highly-penetrant pathogenic allele.

- **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 (below), not from a missing predictor score.
- Conservation: phyloP 0.703, GERP -0.548, phastCons 0.998 — weakly conserved position
- CADD: **PHRED 10.98**. 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: **not assessed** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **12.6%** (mid) · FAF95 11.9% · FAF99 11.6% · 766/6,060 in the highest group · 140,351/1,613,576 alleles overall — common (popmax 12.6%, mid) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 13.7% | 7 |
| Middle Eastern (grpmax) | 12.6% | 8 |
| European (non-Finnish) | 9.66% | 10 |
| South Asian | 9.4% | 11 |
| Remaining individuals (not grpmax-eligible) | 8.59% | 12 |
| Admixed American | 5.68% | 18 |
| Amish (not grpmax-eligible) | 5.15% | 19 |
| Finnish (not grpmax-eligible) | 4.56% | 22 |
| African / African-American | 1.67% | 60 |
| East Asian | 0.029% | 3,453 |

Ashkenazi Jewish 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 **7** 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (7 Benign, 1 Likely benign).

**Submission history:** 8 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2016-03-28 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2016-05-09 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-03-09 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Asphyxiating thoracic dystrophy 3, Jeune thoracic dystrophy, not specified, not provided, AllHighlyPenetrant, 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.

## Similar variants {#similar}

Related DYNC2H1 variant pages (same residue, condition, or type): [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.10695+1G>A](/variant/dync2h1-c-10695-plus-1g-a), [DYNC2H1 c.10813-2A>G](/variant/dync2h1-c-10813-minus-2a-g), [DYNC2H1 c.11493+2T>A](/variant/dync2h1-c-11493-plus-2t-a), [DYNC2H1 c.11650-1G>A](/variant/dync2h1-c-11650-minus-1g-a), [DYNC2H1 c.12156+1G>A](/variant/dync2h1-c-12156-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 301995). 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.*