Is CDH23 p.Arg2066Gln (c.6197G>A) pathogenic?

CDH23 p.Arg2066Gln (c.6197G>A) is classified Benign/Likely benign in CDH23 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0626); Low-frequency (popmax 4.31%, sas); Associated with autosomal recessive nonsyndromic hearing loss 12.

What condition is associated with CDH23 p.Arg2066Gln (c.6197G>A)?

CDH23 p.Arg2066Gln (c.6197G>A) is associated with autosomal recessive nonsyndromic hearing loss 12, Usher syndrome type 1D (ClinVar).

How common is CDH23 p.Arg2066Gln (c.6197G>A) in the general population?

CDH23 p.Arg2066Gln (c.6197G>A) is low-frequency (popmax 4.31%, sas) (gnomAD).

What do computational predictors say about CDH23 p.Arg2066Gln (c.6197G>A)?

AlphaMissense predicts likely benign (score 0.0626) — an in-silico prediction, not a clinical call.

CDH23 p.Arg2066Gln

c.6197G>A · rs201887949 · VCV46006

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0626 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.31%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

autosomal recessive nonsyndromic hearing loss 12

Computational evidence

Protein change
AlphaMissense	0.0626	likely benign
REVEL	0.021	moderately 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 0.61	GERP -3.1, phastCons 0.044
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	2.158	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 4.31% South Asian · 3,925/91,024 alleles

Filtering AF 4.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.15%

Overall 0.261% 4,208/1,613,816 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	4.31%	23
Remaining individualsnot grpmax-eligible	0.266%	376
Middle Eastern	0.165%	606
East Asian	0.0891%	1,122
African / African-American	0.016%	6,250
Admixed American	0.0117%	8,569
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,867
European (non-Finnish)	0.00381%	26,219

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.Arg2066Gln
Coding: c.6197G>A
MANE Select: NM_022124
dbSNP: rs201887949
Type: single nucleotide variant
Location: chr10:71791279 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2066: a UniProt-annotated variant site (in); the cadherin 19 domain

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

Disease context

autosomal recessive nonsyndromic hearing loss 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 1D

Similar variants

CDH23 p.Arg2066Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH23 p.Arg2066= 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-arg2066gln (accessed [today's date]).

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