# NM_022124.6(CDH23):c.2918_2928del (p.Pro973fs)

https://sugi.bio/variant/cdh23-p-pro973fs

## Summary

**CDH23 p.Pro973fs (c.2918_2928del)** is classified **Pathogenic** in CDH23 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-19). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1865731567 · 1 submitter · 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.

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

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDH23](https://sugi.bio/atlas/gene/CDH23/) |
| Protein change (HGVS p.) | p.Pro973fs |
| Coding change (HGVS c.) | c.2918_2928del |
| MANE Select transcript | [NM_022124](https://www.ncbi.nlm.nih.gov/nuccore/NM_022124) |
| dbSNP | [rs1865731567](https://www.ncbi.nlm.nih.gov/snp/rs1865731567/) |
| Variant type | Deletion |
| Location | chr10:71705093-71705103 (GRCh38) |
| ClinVar | [VCV1456656](https://www.ncbi.nlm.nih.gov/clinvar/variation/1456656/) |

**All HGVS expressions:** `NC_000010.10:g.73464852_73464862del`, `NC_000010.11:g.71705095_71705105del`, `NG_008835.1:g.313149_313159del`, `NM_001171930.2:c.2918_2928del`, `NM_001171931.2:c.2918_2928del`, `NM_022124.6:c.2918_2928del`

## 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 4.011, GERP 2.48, phastCons 0.999 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.685, pLI 2.8869e-32. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 25 of 70**, 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}

**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}

Residue **973** lies in the cadherin 9 domain.

**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 2024-09-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-19 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CDH23 variant pages (same residue, condition, or type): [CDH23 c.1143_1176del](/variant/cdh23-c-1143-1176del), [CDH23 c.336+1del](/variant/cdh23-c-336-plus-1del), [CDH23 c.9280_9286del](/variant/cdh23-c-9280-9286del), [CDH23 p.Ala2232_Val2233insTer](/variant/cdh23-p-ala2232-val2233inster), [CDH23 p.Ala2309fs](/variant/cdh23-p-ala2309fs), [CDH23 p.Ala2685fs](/variant/cdh23-p-ala2685fs), [CDH23 p.Arg2115fs](/variant/cdh23-p-arg2115fs), [CDH23 p.Asn1889fs](/variant/cdh23-p-asn1889fs).

### 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 1456656). 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.*