# NM_052844.4(DYNC2I2):c.848G>A (p.Arg283His)

https://sugi.bio/variant/dync2i2-p-arg283his

## Summary

**DYNC2I2 p.Arg283His (c.848G>A)** is classified **Uncertain significance** in DYNC2I2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-01-01). AlphaMissense: likely benign (0.063); Very rare (popmax 8.48e-05%, nfe); Associated with inherited retinal dystrophy.

**At a glance:** Uncertain significance · review: No assertion criteria · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the DYNC2I2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to inherited retinal dystrophy.

*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 | 40 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018916/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.Arg283His |
| Coding change (HGVS c.) | c.848G>A |
| MANE Select transcript | [NM_052844](https://www.ncbi.nlm.nih.gov/nuccore/NM_052844) |
| Variant type | single nucleotide variant |
| Location | chr9:128635225-128635225 (GRCh38) |
| ClinVar | [VCV3249525](https://www.ncbi.nlm.nih.gov/clinvar/variation/3249525/) |

**All HGVS expressions:** `NC_000009.11:g.131397504C>T`, `NC_000009.12:g.128635225C>T`, `NG_027748.1:g.87668C>T`, `NG_027748.2:g.87640C>T`, `NG_034056.1:g.26626G>A`, `NG_085271.1:g.633C>T`, `NM_052844.4:c.848G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.063)
- REVEL 0.058 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.243 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.627, GERP 1.37, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 19.35**. 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 1.02** across the covering region of the MANE Select transcript (128,633,747–128,656,726), spanning 22,979 bp. Chi-square p 0.59. 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>A, Δ0.55 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 **8.48e-05%** (nfe) · 1/1,179,904 in the highest group · 1/1,460,678 alleles overall — very rare (popmax 8.48e-05%, 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}

**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}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2023-01-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Uncertain significance | no assertion criteria provided | clinical testing | 2023-01-01 |

## Associated conditions {#conditions}

[inherited retinal dystrophy](https://sugi.bio/atlas/disease/inherited-retinal-dystrophy/).

**Reported phenotype names (ClinVar):** Retinal dystrophy, Inherited retinal dystrophy.

## Similar variants {#similar}

Related DYNC2I2 variant pages (same residue, condition, or type): [DYNC2I2 p.Arg283Cys](/variant/dync2i2-p-arg283cys), [DYNC2I2 p.Ala500Val](/variant/dync2i2-p-ala500val), [DYNC2I2 p.Ala5Gly](/variant/dync2i2-p-ala5gly), [DYNC2I2 p.Arg330Cys](/variant/dync2i2-p-arg330cys), [DYNC2I2 p.Pro7Ser](/variant/dync2i2-p-pro7ser), [DYNC2I2 p.Ile58Ser](/variant/dync2i2-p-ile58ser), [DYNC2I2 p.Thr228Met](/variant/dync2i2-p-thr228met), [DYNC2I2 p.Asp104Asn](/variant/dync2i2-p-asp104asn).

### 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 3249525). 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.*