# NM_022124.6(CDH23):c.330C>T (p.His110=)

https://sugi.bio/variant/cdh23-p-his110

## Summary

**CDH23 p.His110= (c.330C>T)** is classified **Conflicting classifications of pathogenicity** in CDH23 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-22). Rare (popmax 0.222%, amr); Associated with Usher syndrome type 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs201232514 · 7 submitters · 1 linked condition · rare (popmax 0.222%, amr)

## For patients & families {#patients}

This is a change in the CDH23 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 submitters, and is linked to Usher syndrome type 1.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Worldwide) |
| Diagnostic panels | CDH23 is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Usher syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Sensorineural hearing impairment — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Progressive visual loss — Very frequent (99-80%)
- Blindness — Very frequent (99-80%)
- Nyctalopia — Very frequent (99-80%)
- Visual field defect — Very frequent (99-80%)
- Abnormal vestibular function — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005435/index) · [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.His110= |
| Coding change (HGVS c.) | c.330C>T |
| MANE Select transcript | [NM_022124](https://www.ncbi.nlm.nih.gov/nuccore/NM_022124) |
| dbSNP | [rs201232514](https://www.ncbi.nlm.nih.gov/snp/rs201232514/) |
| Variant type | single nucleotide variant |
| Location | chr10:71510995-71510995 (GRCh38) |
| ClinVar | [VCV499918](https://www.ncbi.nlm.nih.gov/clinvar/variation/499918/) |

**All HGVS expressions:** `NC_000010.10:g.73270752C>T`, `NC_000010.11:g.71510995C>T`, `NG_008835.1:g.119049C>T`, `NM_001171930.2:c.330C>T`, `NM_001171931.2:c.330C>T`, `NM_001171932.2:c.330C>T`, `NM_022124.6:c.330C>T`, `NM_052836.4:c.330C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 1.806, GERP -0.287, phastCons 1 — weakly conserved position
- CADD: **PHRED 15.74**. 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.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.222%** (amr) · FAF95 0.191% · FAF99 0.179% · 133/60,018 in the highest group · 133/1,613,888 alleles overall — rare (popmax 0.222%, 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 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 **110** lies in the cadherin 1 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-22.

**Submitter consensus:** conflicting (5 Likely benign, 1 Uncertain significance, 1 Benign).

**Submission history:** 7 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-08-07 |
| Natera, Inc. | Likely benign | no assertion criteria provided | clinical testing | 2020-05-13 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-01-26 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-22 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-11-18 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-06 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-10-25 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** not provided, Usher syndrome type 1, CDH23-related disorder, not specified, CDH23-related condition, CDH23-related disorders, none provided, AllHighlyPenetrant, RETINITIS PIGMENTOSA AND CONGENITAL DEAFNESS.

## Similar variants {#similar}

Related CDH23 variant pages (same residue, condition, or type): [CDH23 p.His110Arg](/variant/cdh23-p-his110arg), [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.Arg301Gln](/variant/cdh23-p-arg301gln), [CDH23 p.Arg3189Gln](/variant/cdh23-p-arg3189gln).

### 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 499918). 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.*