Is CDH23 p.Val2127Phe (c.6379G>T) pathogenic?

CDH23 p.Val2127Phe (c.6379G>T) is classified Likely pathogenic in CDH23 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-02). AlphaMissense: ambiguous (0.4417); Very rare (popmax 0.00517%, nfe); Associated with autosomal recessive nonsyndromic hearing loss 12.

What condition is associated with CDH23 p.Val2127Phe (c.6379G>T)?

CDH23 p.Val2127Phe (c.6379G>T) is associated with autosomal recessive nonsyndromic hearing loss 12 (ClinVar).

How common is CDH23 p.Val2127Phe (c.6379G>T) in the general population?

CDH23 p.Val2127Phe (c.6379G>T) is very rare (popmax 0.00517%, nfe) (gnomAD).

What do computational predictors say about CDH23 p.Val2127Phe (c.6379G>T)?

AlphaMissense predicts ambiguous (score 0.4417) — an in-silico prediction, not a clinical call.

CDH23 p.Val2127Phe

c.6379G>T · rs765026901 · VCV1699473

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4417 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00517%, nfe)

Conditions

autosomal recessive nonsyndromic hearing loss 12

Computational evidence

Protein change
AlphaMissense	0.4417	ambiguous
REVEL	0.688	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	22.1	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 0.00517% European (non-Finnish) · 61/1,179,888 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00424% 62/1,461,706 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00517%	19,342
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Val2127Phe
Coding: c.6379G>T
MANE Select: NM_022124
dbSNP: rs765026901
Type: single nucleotide variant
Location: chr10:71793307 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2127: the cadherin 20 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

Similar variants

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 p.Ala3190Val Uncertain significance ★★★ ⚠ same condition
CDH23 p.Arg301Gln Uncertain significance ★★★ same condition
CDH23 p.Arg3189Trp Uncertain significance ★★★ ⚠ same condition
CDH23 p.Asn2289Ser 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-val2127phe (accessed [today's date]).

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