Is CDH23 p.Arg90Gln (c.269G>A) pathogenic?

CDH23 p.Arg90Gln (c.269G>A) is classified Uncertain significance in CDH23 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-09-09). AlphaMissense: likely benign (0.2181); Very rare (popmax 0.00769%, sas); Associated with pituitary adenoma 5, multiple types.

What condition is associated with CDH23 p.Arg90Gln (c.269G>A)?

CDH23 p.Arg90Gln (c.269G>A) is associated with pituitary adenoma 5, multiple types, Usher syndrome type 1, Usher syndrome type 1D (ClinVar).

How common is CDH23 p.Arg90Gln (c.269G>A) in the general population?

CDH23 p.Arg90Gln (c.269G>A) is very rare (popmax 0.00769%, sas) (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.Arg90Gln (c.269G>A)?

AlphaMissense predicts likely benign (score 0.2181) — an in-silico prediction, not a clinical call.

CDH23 p.Arg90Gln

c.269G>A · rs397517317 · VCV45899

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2181 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

pituitary adenoma 5, multiple types

Computational evidence

Protein change
AlphaMissense	0.2181	likely benign
REVEL	0.222	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00769% South Asian · 7/91,074 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00198% 32/1,613,694 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,011
Admixed American	0.005%	20,008
East Asian	0.00446%	22,435
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
European (non-Finnish)	0.00161%	62,097

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.Arg90Gln
Coding: c.269G>A
MANE Select: NM_022124
dbSNP: rs397517317
Type: single nucleotide variant
Location: chr10:71510205 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 90: the cadherin 1 domain

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.Arg90Trp Uncertain significance ★★ same residue
CDH23 p.Arg90= Likely benign ★ 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
CDH23 p.Ala3190Val 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-arg90gln (accessed [today's date]).

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