# NM_052844.4(DYNC2I2):c.629del (p.Pro210fs)

https://sugi.bio/variant/dync2i2-p-pro210fs

## Summary

**DYNC2I2 p.Pro210fs (c.629del)** is classified **Pathogenic/Likely pathogenic** in DYNC2I2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-11). No gnomAD frequency available for this variant; Associated with short-rib thoracic dysplasia 11 with or without polydactyly.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs2132146546 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DYNC2I2 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to short-rib thoracic dysplasia 11 with or without polydactyly.

*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/0015996/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DYNC2I2](https://sugi.bio/atlas/gene/DYNC2I2/) |
| Protein change (HGVS p.) | p.Pro210fs |
| Coding change (HGVS c.) | c.629del |
| MANE Select transcript | [NM_052844](https://www.ncbi.nlm.nih.gov/nuccore/NM_052844) |
| dbSNP | [rs2132146546](https://www.ncbi.nlm.nih.gov/snp/rs2132146546/) |
| Variant type | Deletion |
| Location | chr9:128636355-128636355 (GRCh38) |
| ClinVar | [VCV1325354](https://www.ncbi.nlm.nih.gov/clinvar/variation/1325354/) |

**All HGVS expressions:** `NC_000009.11:g.131398635del`, `NC_000009.12:g.128636356del`, `NG_034056.1:g.25496del`, `NM_052844.4:c.629del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -13.104, GERP -3.68 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.036, pLI 8.6153e-12. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 9**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**DYNC2I2** population constraint: LOEUF 1.036, pLI 8.6153e-12, missense-Z -0.55611. *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):

- **short-rib thoracic dysplasia 11 with or without polydactyly** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.66, 65% of residues very-high.

**4 experimental structure(s)** (PDB): [6RLB](https://www.rcsb.org/structure/6RLB), [6SC2](https://www.rcsb.org/structure/6SC2), [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 DYNC2I2 (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.*

**How this variant is thought to act:** DYNC2I2's established molecular role includes dynein light chain binding.


### Pathways affected {#pathways}

DYNC2I2 participates in **1 Reactome pathway** (⚕ = disease pathway):

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

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

**Molecular function:** dynein light chain binding.

**Biological process:** intraciliary retrograde transport, cilium assembly.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-11.

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

**Submission history:** 2 submissions (2019–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-12-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-11 |

## Associated conditions {#conditions}

[short-rib thoracic dysplasia 11 with or without polydactyly](https://sugi.bio/atlas/disease/short-rib-thoracic-dysplasia-11-with-or-without-polydactyly/).

**Reported phenotype names (ClinVar):** Short-rib thoracic dysplasia 11 with or without polydactyly, SHORT-RIB THORACIC DYSPLASIA 11 WITHOUT POLYDACTYLY.

## Similar variants {#similar}

Related DYNC2I2 variant pages (same residue, condition, or type): [DYNC2I2 p.Pro210Arg](/variant/dync2i2-p-pro210arg), [DYNC2I2 p.Pro210=](/variant/dync2i2-p-pro210), [DYNC2I2 p.Pro210Leu](/variant/dync2i2-p-pro210leu), [DYNC2I2 p.Leu438fs](/variant/dync2i2-p-leu438fs), [DYNC2I2 p.Phe439fs](/variant/dync2i2-p-phe439fs), [DYNC2I2 p.Pro32fs](/variant/dync2i2-p-pro32fs), [DYNC2I2 c.1372+5del](/variant/dync2i2-c-1372-plus-5del), [DYNC2I2 c.546-1_547del](/variant/dync2i2-c-546-minus-1-547del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 1325354). 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.*