# NM_001377.3(DYNC2H1):c.6035C>T (p.Ala2012Val)

https://sugi.bio/variant/dync2h1-p-ala2012val

## Summary

**DYNC2H1 p.Ala2012Val (c.6035C>T)** is classified **Likely pathogenic** in DYNC2H1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-17). AlphaMissense: likely pathogenic (0.8606); Very rare (popmax 0.000254%, nfe); Associated with asphyxiating thoracic dystrophy 3.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1215030552 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the DYNC2H1 gene that is considered likely disease-causing, submitted by 1 submitter, 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.Ala2012Val |
| Coding change (HGVS c.) | c.6035C>T |
| MANE Select transcript | [NM_001377](https://www.ncbi.nlm.nih.gov/nuccore/NM_001377) |
| dbSNP | [rs1215030552](https://www.ncbi.nlm.nih.gov/snp/rs1215030552/) |
| Variant type | single nucleotide variant |
| Location | chr11:103177716-103177716 (GRCh38) |
| ClinVar | [VCV3064165](https://www.ncbi.nlm.nih.gov/clinvar/variation/3064165/) |

**All HGVS expressions:** `NC_000011.10:g.103177716C>T`, `NC_000011.9:g.103048445C>T`, `NG_016423.2:g.73286C>T`, `NM_001080463.2:c.6035C>T`, `NM_001377.3:c.6035C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8606) — concordant with the pathogenic call
- REVEL 0.89 (moderately pathogenic-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this damaging; SaProt makes no call
- Conservation: phyloP 7.614, GERP 1.61, 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 28.7**. 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 0.74** across the covering region of the MANE Select transcript (103,177,581–103,186,274), spanning 8,693 bp. Chi-square p 6.7e-06. 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>G, Δ0.38 acceptor 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 **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,179,688 in the highest group · 3/1,613,488 alleles overall — very rare (popmax 0.000254%, nfe).

*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 **2012** lies in a turn; the 'aaa 2' 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-17.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | criteria provided, single submitter | research | 2024-03-17 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Asphyxiating thoracic dystrophy 3, 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 p.Ala2012Thr](/variant/dync2h1-p-ala2012thr), [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), [DYNC2H1 c.1662-2A>G](/variant/dync2h1-c-1662-minus-2a-g), [DYNC2H1 c.2106+2T>C](/variant/dync2h1-c-2106-plus-2t-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 3064165). 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.*