# NM_022124.5(CDH23):c.337del

https://sugi.bio/variant/cdh23-c-337del

## Summary

**CDH23 c.337del** is classified **Pathogenic** in CDH23 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-15). No gnomAD frequency available for this variant; Associated with Usher syndrome type 1D.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2132200416 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CDH23 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Usher syndrome type 1D.

*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 | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005438/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDH23](https://sugi.bio/atlas/gene/CDH23/) |
| Coding change (HGVS c.) | c.337del |
| MANE Select transcript | [NM_022124](https://www.ncbi.nlm.nih.gov/nuccore/NM_022124) |
| dbSNP | [rs2132200416](https://www.ncbi.nlm.nih.gov/snp/rs2132200416/) |
| Variant type | Deletion |
| Location | chr10:71511119-71511119 (GRCh38) |
| ClinVar | [VCV1185586](https://www.ncbi.nlm.nih.gov/clinvar/variation/1185586/) |

**All HGVS expressions:** `NC_000010.10:g.73270877del`, `NC_000010.11:g.71511120del`, `NG_008835.1:g.119174del`

## 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 11.206, GERP 1.92, phastCons 1 — highly conserved position (PP3-type support)
- Non-coding constraint (Gnocchi): **Z 3.01**, o/e 0.79 (1 kb window 71,511,000–71,512,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- 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}

**CDH23** population constraint: LOEUF 0.685, pLI 2.8869e-32, missense-Z 1.6119; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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):

- **nonsyndromic genetic hearing loss** — Definitive (AR)

## Protein context {#protein}


**6 experimental structure(s)** (PDB): [2KBR](https://www.rcsb.org/structure/2KBR), [2KBS](https://www.rcsb.org/structure/2KBS), [2LSR](https://www.rcsb.org/structure/2LSR), [5TFM](https://www.rcsb.org/structure/5TFM), [5VVM](https://www.rcsb.org/structure/5VVM), [5WJ8](https://www.rcsb.org/structure/5WJ8).

## What this gene does {#gene-function}

*Describes the biological roles of CDH23 (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}

CDH23 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Sensory processing of sound by inner hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662360) | electronic |
| [Sensory processing of sound by outer hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662361) | electronic |

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

**Biological process:** calcium ion transport, sensory perception of sound, photoreceptor cell maintenance, sensory perception of light stimulus, equilibrioception, regulation of cytosolic calcium ion concentration.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-07-15.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| INGEBI, INGEBI / CONICET | Pathogenic | criteria provided, single submitter | clinical testing | 2021-07-15 |

## Associated conditions {#conditions}

[Usher syndrome type 1D](https://sugi.bio/atlas/disease/usher-syndrome-type-1d/).

**Reported phenotype names (ClinVar):** Usher syndrome type 1D, USHER SYNDROME, TYPE ID.

## Similar variants {#similar}

Related CDH23 variant pages (same residue, condition, or type): [CDH23 c.1143_1176del](/variant/cdh23-c-1143-1176del), [CDH23 c.9280_9286del](/variant/cdh23-c-9280-9286del), [CDH23 p.Ala2232_Val2233insTer](/variant/cdh23-p-ala2232-val2233inster), [CDH23 p.Ile2132fs](/variant/cdh23-p-ile2132fs), [CDH23 p.Leu2785fs](/variant/cdh23-p-leu2785fs), [CDH23 p.Leu3085fs](/variant/cdh23-p-leu3085fs), [CDH23 p.Leu826fs](/variant/cdh23-p-leu826fs), [CDH23 p.Lys2278fs](/variant/cdh23-p-lys2278fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 1185586). 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.*