# NM_022124.6(CDH23):c.4988A>G (p.Asp1663Gly)

https://sugi.bio/variant/cdh23-p-asp1663gly

## Summary

**CDH23 p.Asp1663Gly (c.4988A>G)** is classified **Uncertain significance** in CDH23 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-12). AlphaMissense: likely pathogenic (0.9415); Very rare (popmax 0.00667%, amr).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs747087196 · 3 submitters · AlphaMissense likely pathogenic · very rare (popmax 0.00667%, amr)

## For patients & families {#patients}

This is a change in the CDH23 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters.

*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.Asp1663Gly |
| Coding change (HGVS c.) | c.4988A>G |
| MANE Select transcript | [NM_022124](https://www.ncbi.nlm.nih.gov/nuccore/NM_022124) |
| dbSNP | [rs747087196](https://www.ncbi.nlm.nih.gov/snp/rs747087196/) |
| Variant type | single nucleotide variant |
| Location | chr10:71777822-71777822 (GRCh38) |
| ClinVar | [VCV1399191](https://www.ncbi.nlm.nih.gov/clinvar/variation/1399191/) |

**All HGVS expressions:** `NC_000010.10:g.73537579A>G`, `NC_000010.11:g.71777822A>G`, `NG_008835.1:g.385876A>G`, `NM_022124.5:c.4988A>G`, `NM_022124.6:c.4988A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9415)
- REVEL 0.851 (moderately pathogenic-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this damaging; SaProt makes no call
- SpliceAI predicts **donor gain** (Δ 0.35) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.181, GERP 1.9, phastCons 1 — highly conserved (agrees)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- CADD: **PHRED 32.0**. 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 0.96** across the covering region of the MANE Select transcript (71,439,832–71,798,551), spanning 358,719 bp. Chi-square p 0.017. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.35**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.35**.
- Population frequency (gnomAD v4.1): grpmax **0.00667%** (amr) · FAF95 0.00226% · FAF99 0.00135% · 4/59,996 in the highest group · 4/1,613,818 alleles overall — very rare (popmax 0.00667%, amr).

*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 gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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 **1663** lies in the cadherin 16 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-07-12.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2019–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-07-12 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-12 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-09-23 |

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

## Similar variants {#similar}

Related CDH23 variant pages (same residue, condition, or type): [CDH23 p.Asp1663Asn](/variant/cdh23-p-asp1663asn), [CDH23 p.Arg2029Trp](/variant/cdh23-p-arg2029trp), [CDH23 p.Asp127Gly](/variant/cdh23-p-asp127gly), [CDH23 p.Glu956Lys](/variant/cdh23-p-glu956lys), [CDH23 p.Pro240Leu](/variant/cdh23-p-pro240leu), [CDH23 c.1515-12G>A](/variant/cdh23-c-1515-minus-12g-a), [CDH23 p.Ala3190Val](/variant/cdh23-p-ala3190val), [CDH23 p.Arg301Gln](/variant/cdh23-p-arg301gln).

### 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 1399191). 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.*