# NM_001377.3(DYNC2H1):c.1969A>C (p.Ser657Arg)

https://sugi.bio/variant/dync2h1-p-ser657arg

## Summary

**DYNC2H1 p.Ser657Arg (c.1969A>C)** is classified **Uncertain significance** in DYNC2H1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-07). AlphaMissense: likely benign (0.1874); Very rare (popmax 0.00511%, amr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00511%, amr)

## For patients & families {#patients}

This is a change in the DYNC2H1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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 | [DYNC2H1](https://sugi.bio/atlas/gene/DYNC2H1/) |
| Protein change (HGVS p.) | p.Ser657Arg |
| Coding change (HGVS c.) | c.1969A>C |
| MANE Select transcript | [NM_001377](https://www.ncbi.nlm.nih.gov/nuccore/NM_001377) |
| Variant type | single nucleotide variant |
| Location | chr11:103133570-103133570 (GRCh38) |
| ClinVar | [VCV3274175](https://www.ncbi.nlm.nih.gov/clinvar/variation/3274175/) |

**All HGVS expressions:** `NC_000011.10:g.103133570A>C`, `NC_000011.9:g.103004299A>C`, `NG_016423.2:g.29140A>C`, `NM_001080463.2:c.1969A>C`, `NM_001377.3:c.1969A>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1874)
- REVEL 0.181 (moderately benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- SpliceAI predicts **acceptor gain** (Δ 0.26) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.56, GERP 2.39, phastCons 1 — highly conserved (differs from AlphaMissense)
- **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 21.7**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.26**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.26**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00511%** (amr) · FAF95 0.00136% · FAF99 0.000676% · 3/58,712 in the highest group · 5/1,608,298 alleles overall — very rare (popmax 0.00511%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00511% | 19,571 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,280 |
| European (non-Finnish) | 8.48e-05% | 1,178,650 |

*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 **657** 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-06-07.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-07 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related DYNC2H1 variant pages (same residue, condition, or type): [DYNC2H1 p.Ala1794Ser](/variant/dync2h1-p-ala1794ser), [DYNC2H1 p.Ala1941Pro](/variant/dync2h1-p-ala1941pro), [DYNC2H1 p.Ala2961Val](/variant/dync2h1-p-ala2961val), [DYNC2H1 p.Ala3172Ser](/variant/dync2h1-p-ala3172ser), [DYNC2H1 p.Ala4003Gly](/variant/dync2h1-p-ala4003gly), [DYNC2H1 p.Arg1043Cys](/variant/dync2h1-p-arg1043cys), [DYNC2H1 p.Arg1153Gln](/variant/dync2h1-p-arg1153gln), [DYNC2H1 p.Arg1253Gln](/variant/dync2h1-p-arg1253gln).

### 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 3274175). 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.*