# NM_001377.3(DYNC2H1):c.988C>T (p.Arg330Cys)

https://sugi.bio/variant/dync2h1-p-arg330cys

## Summary

**DYNC2H1 p.Arg330Cys (c.988C>T)** is classified **Pathogenic/Likely pathogenic** in DYNC2H1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-01). AlphaMissense: likely pathogenic (0.6823); Very rare (popmax 0.00835%, amr); Associated with Jeune syndrome.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs397514637 · 7 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00835%, amr)

## For patients & families {#patients}

This is a change in the DYNC2H1 gene that is considered likely disease-causing, submitted by 7 submitters, and is linked to Jeune 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.*

|  |  |
| --- | --- |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003049/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.Arg330Cys |
| Coding change (HGVS c.) | c.988C>T |
| MANE Select transcript | [NM_001377](https://www.ncbi.nlm.nih.gov/nuccore/NM_001377) |
| dbSNP | [rs397514637](https://www.ncbi.nlm.nih.gov/snp/rs397514637/) |
| Variant type | single nucleotide variant |
| Location | chr11:103117852-103117852 (GRCh38) |
| ClinVar | [VCV40070](https://www.ncbi.nlm.nih.gov/clinvar/variation/40070/) |

**All HGVS expressions:** `NC_000011.10:g.103117852C>T`, `NC_000011.9:g.102988581C>T`, `NG_016423.2:g.13422C>T`, `NM_001080463.2:c.988C>T`, `NM_001377.3:c.988C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6823) — concordant with the pathogenic call
- REVEL 0.641 (indeterminate)
- Conservation: phyloP 7.571, GERP 2.23, 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 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 0.99** across the covering region of the MANE Select transcript (103,109,575–103,170,212), spanning 60,637 bp. Chi-square p 0.56. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for DYNC2H1 (4,790 scored positions, the nearest 4 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.00835%** (amr) · FAF95 0.00324% · FAF99 0.00207% · 5/59,872 in the highest group · 29/1,610,370 alleles overall — very rare (popmax 0.00835%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00835% | 11,974 |
| African / African-American | 0.00533% | 18,751 |
| East Asian | 0.00446% | 22,413 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00339% | 29,490 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,332 |
| European (non-Finnish) | 0.00127% | 78,535 |
| South Asian | 0.0011% | 90,542 |

*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 **330** lies in the 'stem' region; a UniProt-annotated variant site (in srtd3).

**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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (5 Pathogenic, 4 Likely pathogenic).

**Submission history:** 9 submissions (2012–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2012-04-01 |
| Otogenetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Dan Cohn Lab, University Of California Los Angeles | Pathogenic | no assertion criteria provided | research | 2017-06-01 |
| University of Washington Center for Mendelian Genomics, University of Washington | Likely pathogenic | no assertion criteria provided | research |  |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-09-13 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-05-24 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-12 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Jeune thoracic dystrophy, Asphyxiating thoracic dystrophy 3, Jeune syndrome, Infantile thoracic dystrophy, Thoracic pelvic phalangeal dystrophy, Jeune's syndrome, Chondroectodermal dysplasia-like syndrome, Short-rib thoracic dysplasia, SHORT-RIB THORACIC DYSPLASIA 3 WITH OR WITHOUT POLYDACTYLY, POLYDACTYLY WITH NEONATAL CHONDRODYSTROPHY, TYPE I.

## Same-residue context {#hotspot}

Residue **330** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [DYNC2H1 p.Arg330Leu](/variant/dync2h1-p-arg330leu), [DYNC2H1 p.Arg330His](/variant/dync2h1-p-arg330his). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DYNC2H1 variant pages (same residue, condition, or type): [DYNC2H1 p.Arg330His](/variant/dync2h1-p-arg330his), [DYNC2H1 p.Arg330Leu](/variant/dync2h1-p-arg330leu), [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).

### 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 40070). 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.*