Is CDH23 p.Asn1845Ser (c.5534A>G) pathogenic?

CDH23 p.Asn1845Ser (c.5534A>G) is classified Conflicting classifications of pathogenicity in CDH23 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-10). AlphaMissense: likely pathogenic (0.64); Very rare (popmax 0.00223%, eas); Associated with Usher syndrome.

What condition is associated with CDH23 p.Asn1845Ser (c.5534A>G)?

CDH23 p.Asn1845Ser (c.5534A>G) is associated with Usher syndrome, pituitary adenoma 5, multiple types (ClinVar).

How common is CDH23 p.Asn1845Ser (c.5534A>G) in the general population?

CDH23 p.Asn1845Ser (c.5534A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Usher syndrome inherited?

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

What do computational predictors say about CDH23 p.Asn1845Ser (c.5534A>G)?

AlphaMissense predicts likely pathogenic (score 0.64) — an in-silico prediction, not a clinical call.

CDH23 p.Asn1845Ser

c.5534A>G · rs1275390489 · VCV2680454

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.64 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

Usher syndrome

Computational evidence

Protein change
AlphaMissense	0.64	likely pathogenic
REVEL	0.833	moderately pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	26.2	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 0.00223% East Asian · 1/44,880 alleles

Overall 0.000372% 6/1,613,834 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00625%	16,004
East Asiangrpmax	0.00223%	44,880
European (non-Finnish)	8.48e-05%	1,179,901

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.Asn1845Ser
Coding: c.5534A>G
MANE Select: NM_022124
dbSNP: rs1275390489
Type: single nucleotide variant
Location: chr10:71784922 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1845: the cadherin 17 domain

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

Disease context

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

Also linked: pituitary adenoma 5, multiple types

For Usher syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

CDH23 p.Asn1845Lys Pathogenic same residue
CDH23 p.Asn1845= 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-asn1845ser (accessed [today's date]).

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