Is PCDH15 p.Cys1663fs (c.4987dup) pathogenic?

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.

What condition is associated with PCDH15 p.Cys1663fs (c.4987dup)?

PCDH15 p.Cys1663fs (c.4987dup) is associated with Usher syndrome type 1F (ClinVar).

How common is PCDH15 p.Cys1663fs (c.4987dup) in the general population?

PCDH15 p.Cys1663fs (c.4987dup) is very rare (popmax 0.00254%, nfe) (gnomAD).

PCDH15 p.Cys1663fs

c.4987dup · rs775238614 · VCV553676

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

Conditions

Usher syndrome type 1F

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP 2.2, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00254% European (non-Finnish) · 30/1,179,956 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00186% 30/1,614,042 alleles · very rare exomes 30/1,461,828 · genomes 0/152,214 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PCDH15
Protein: p.Cys1663fs
Coding: c.4987dup
MANE Select: NM_001384140 · reported on NM_033056
dbSNP: rs775238614
Type: Duplication
Location: chr10:53822738 (GRCh38)
Gene constraint: LOEUF 0.819 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 66.05 · 8 PDB
Residue 1663: a UniProt-annotated variant site (in dfnb23)

Full PCDH15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Usher syndrome type 1F — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PCDH15 c.3717+2dup Pathogenic/Likely pathogenic ★★ same condition
PCDH15 c.4671+1429_4671+1432dup Pathogenic/Likely pathogenic ★★ same condition
PCDH15 p.Ala1510fs Pathogenic/Likely pathogenic ★★ same condition
PCDH15 p.Ala1524fs Pathogenic/Likely pathogenic ★★ same condition
PCDH15 p.Ala306fs Likely pathogenic ★★ same condition
PCDH15 p.Asn1254fs Pathogenic/Likely pathogenic ★★ same condition
PCDH15 p.Asp1518delinsIleTer Pathogenic/Likely pathogenic ★★ same condition
PCDH15 p.Glu188fs Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pcdh15-p-cys1663fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown