# NM_052844.4(DYNC2I2):c.1193_1194del (p.Val398fs)

https://sugi.bio/variant/dync2i2-p-val398fs

## Summary

**DYNC2I2 p.Val398fs (c.1193_1194del)** is classified **Pathogenic** in DYNC2I2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-24). Very rare (popmax 0.00116%, sas); Associated with short-rib thoracic dysplasia 11 with or without polydactyly.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00116%, sas)

## For patients & families {#patients}

This is a change in the DYNC2I2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, 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.Val398fs |
| Coding change (HGVS c.) | c.1193_1194del |
| MANE Select transcript | [NM_052844](https://www.ncbi.nlm.nih.gov/nuccore/NM_052844) |
| Variant type | Microsatellite |
| Location | chr9:128634709-128634710 (GRCh38) |
| ClinVar | [VCV4532118](https://www.ncbi.nlm.nih.gov/clinvar/variation/4532118/) |

**All HGVS expressions:** `NC_000009.11:g.131396988CA[1]`, `NC_000009.12:g.128634709CA[1]`, `NG_027748.1:g.87152CA[1]`, `NG_027748.2:g.87124CA[1]`, `NG_034056.1:g.27139TG[1]`, `NG_085271.1:g.117CA[1]`, `NM_052844.4:c.1193_1194del`

## Computational & population evidence {#evidence}

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

- **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 7.763, GERP 1.49, phastCons 1 — highly conserved position (PP3-type support)
- 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 7 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 microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00116%** (sas) · 1/86,274 in the highest group · 3/1,577,748 alleles overall — very rare (popmax 0.00116%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00164% | 60,994 |
| South Asian (grpmax) | 0.00116% | 86,274 |
| European (non-Finnish) | 8.61e-05% | 1,161,946 |

Finnish 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}

**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** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-24.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-24 |

## 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.Glu368fs](/variant/dync2i2-p-glu368fs), [DYNC2I2 p.Arg373fs](/variant/dync2i2-p-arg373fs), [DYNC2I2 p.Thr473fs](/variant/dync2i2-p-thr473fs), [DYNC2I2 p.Thr514fs](/variant/dync2i2-p-thr514fs), [DYNC2I2 p.Gln144dup](/variant/dync2i2-p-gln144dup), [DYNC2I2 c.1373-12CT[2]](/variant/dync2i2-c-1373-minus-12ct-2), [DYNC2I2 c.1372+1G>A](/variant/dync2i2-c-1372-plus-1g-a), [DYNC2I2 p.Arg121Ter](/variant/dync2i2-p-arg121ter).

### 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 2026-10-14); 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 4532118). 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.*