Is CDH23 p.Arg3341Cys (c.10021C>T) pathogenic?

CDH23 p.Arg3341Cys (c.10021C>T) is classified Conflicting classifications of pathogenicity in CDH23 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2025-11-08). AlphaMissense: ambiguous (0.3551); Ultra-rare (popmax 0.0203%, nfe); Associated with pituitary adenoma 5, multiple types.

What condition is associated with CDH23 p.Arg3341Cys (c.10021C>T)?

CDH23 p.Arg3341Cys (c.10021C>T) is associated with pituitary adenoma 5, multiple types, Usher syndrome type 1, Usher syndrome type 1D (ClinVar).

How common is CDH23 p.Arg3341Cys (c.10021C>T) in the general population?

CDH23 p.Arg3341Cys (c.10021C>T) is ultra-rare (popmax 0.0203%, nfe) (gnomAD).

How is Familial isolated pituitary adenoma inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDH23 p.Arg3341Cys (c.10021C>T)?

AlphaMissense predicts ambiguous (score 0.3551) — an in-silico prediction, not a clinical call.

CDH23 p.Arg3341Cys

c.10021C>T · rs370074117 · VCV198640

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

ambiguous

0.3551 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0203%, nfe)

Conditions

pituitary adenoma 5, multiple types

Computational evidence

Protein change
AlphaMissense	0.3551	ambiguous
REVEL	0.198	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 12 kb · p 0.86 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0203% European (non-Finnish) · 237/1,165,656 alleles

Filtering AF 0.0182% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0174%

Overall 0.0191% 305/1,593,886 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0655%	1,526
Remaining individualsnot grpmax-eligible	0.0211%	4,734
European (non-Finnish)grpmax	0.0203%	4,918
Middle Eastern	0.0167%	6,004
Admixed American	0.00843%	11,866
South Asian	0.00667%	15,002
Ashkenazi Jewishnot grpmax-eligible	0.00346%	28,930
East Asian	0.00225%	44,464

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CDH23
Protein: p.Arg3341Cys
Coding: c.10021C>T
MANE Select: NM_022124
dbSNP: rs370074117
Type: single nucleotide variant
Location: chr10:71815234 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

Full CDH23 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pituitary adenoma 5, multiple types — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 1 Usher syndrome type 1D autosomal recessive nonsyndromic hearing loss 12 inherited retinal dystrophy

For Familial isolated pituitary adenoma (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Elderly, Infancy

Similar variants

CDH23 p.Arg3341His Uncertain significance ★★ ⚠ same residue
CDH23 p.Arg3341= Conflicting classifications of pathogenicity ★ same residue
CDH23 p.Arg3341Gly Uncertain significance ★ ⚠ same residue
CDH23 p.Arg2029Trp Pathogenic ★★★ ⚠ same condition
CDH23 p.Asp127Gly Likely pathogenic ★★★ same condition
CDH23 p.Glu956Lys Pathogenic ★★★ same condition
CDH23 p.Pro240Leu Pathogenic ★★★ same condition
CDH23 c.1515-12G>A Uncertain significance ★★★ 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/cdh23-p-arg3341cys (accessed [today's date]).

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