# NM_033056.4(PCDH15):c.4987dup (p.Cys1663fs)

https://sugi.bio/variant/pcdh15-p-cys1663fs

## Summary

**PCDH15 p.Cys1663fs (c.4987dup)** is classified **Uncertain significance** in PCDH15 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-09-06). Very rare (popmax 0.00254%, nfe); Associated with Usher syndrome type 1F.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs775238614 · 2 submitters · 1 linked condition · very rare (popmax 0.00254%, nfe)

## For patients & families {#patients}

This is a change in the PCDH15 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Usher syndrome type 1F.

*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/0010043/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PCDH15](https://sugi.bio/atlas/gene/PCDH15/) |
| Protein change (HGVS p.) | p.Cys1663fs |
| Coding change (HGVS c.) | c.4987dup |
| MANE Select transcript | [NM_001384140](https://www.ncbi.nlm.nih.gov/nuccore/NM_001384140) (variant reported on NM_033056) |
| dbSNP | [rs775238614](https://www.ncbi.nlm.nih.gov/snp/rs775238614/) |
| Variant type | Duplication |
| Location | chr10:53822738-53822739 (GRCh38) |
| ClinVar | [VCV553676](https://www.ncbi.nlm.nih.gov/clinvar/variation/553676/) |

**All HGVS expressions:** `NC_000010.10:g.55582502dup`, `NC_000010.11:g.53822742dup`, `NG_009191.3:g.1811444dup`, `NM_001142763.2:c.5008dup`, `NM_001142764.2:c.4993dup`, `NM_001142765.2:c.4780dup`, `NM_001142766.2:c.4978dup`, `NM_001142767.2:c.4867dup`, `NM_001142768.2:c.4927dup`, `NM_001142769.3:c.4409+2397dup`, `NM_001142770.3:c.4373+2397dup`, `NM_001142771.2:c.4388+2397dup`, `NM_001142772.2:c.4373+2397dup`, `NM_001142773.2:c.4918dup`, `NM_001354404.2:c.4921dup`, `NM_001354411.2:c.4388+4654dup`, `NM_001354420.2:c.4367+4654dup`, `NM_001354429.2:c.4367+4654dup`, `NM_001384140.1:c.4368-2509dup`, `NM_033056.3:c.4987dupT`, `NM_033056.4:c.4987dup`

## 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 4.899, GERP 2.19, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.819, pLI 8.4349e-24. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00254%** (nfe) · FAF95 0.0018% · FAF99 0.00156% · 30/1,179,956 in the highest group · 30/1,614,042 alleles overall — very rare (popmax 0.00254%, 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}

**PCDH15** population constraint: LOEUF 0.819, pLI 8.4349e-24, missense-Z -0.14461; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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** — Limited (AR)

## Protein context {#protein}

Residue **1663** lies in a UniProt-annotated variant site (in dfnb23).

AlphaFold model confidence (whole protein): pLDDT 66.05, 9% of residues very-high.

**8 experimental structure(s)** (PDB): [4XHZ](https://www.rcsb.org/structure/4XHZ), [5T4M](https://www.rcsb.org/structure/5T4M), [5T4N](https://www.rcsb.org/structure/5T4N), [5ULY](https://www.rcsb.org/structure/5ULY), [6E8F](https://www.rcsb.org/structure/6E8F), [6EB5](https://www.rcsb.org/structure/6EB5) — incl. mutant structure 5T4N.

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

*Describes the biological roles of PCDH15 (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}

PCDH15 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) | other |
| [Sensory processing of sound by outer hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662361) | other |

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

**Biological process:** sensory perception of sound, photoreceptor cell maintenance, sensory perception of light stimulus, equilibrioception.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-06.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2017–2022); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2017-09-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-09-06 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Usher syndrome type 1F, not provided, USHER SYNDROME, TYPE IF, none provided.

## Similar variants {#similar}

Related PCDH15 variant pages (same residue, condition, or type): [PCDH15 c.3717+2dup](/variant/pcdh15-c-3717-plus-2dup), [PCDH15 c.4671+1429_4671+1432dup](/variant/pcdh15-c-4671-plus-1429-4671-plus-1432dup), [PCDH15 p.Ala1510fs](/variant/pcdh15-p-ala1510fs), [PCDH15 p.Ala1524fs](/variant/pcdh15-p-ala1524fs), [PCDH15 p.Ala306fs](/variant/pcdh15-p-ala306fs), [PCDH15 p.Asn1254fs](/variant/pcdh15-p-asn1254fs), [PCDH15 p.Asp1518delinsIleTer](/variant/pcdh15-p-asp1518delinsileter), [PCDH15 p.Glu188fs](/variant/pcdh15-p-glu188fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 553676). 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.*