Is CDH23 p.Phe1012Ser (c.3035T>C) pathogenic?

CDH23 p.Phe1012Ser (c.3035T>C) is classified Uncertain significance in CDH23 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-06-13). AlphaMissense: likely benign (0.2654); Very rare (popmax 0.00484%, nfe); Associated with Usher syndrome type 1.

What condition is associated with CDH23 p.Phe1012Ser (c.3035T>C)?

CDH23 p.Phe1012Ser (c.3035T>C) is associated with Usher syndrome type 1 (ClinVar).

How common is CDH23 p.Phe1012Ser (c.3035T>C) in the general population?

CDH23 p.Phe1012Ser (c.3035T>C) is very rare (popmax 0.00484%, nfe) (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.Phe1012Ser (c.3035T>C)?

AlphaMissense predicts likely benign (score 0.2654) — an in-silico prediction, not a clinical call.

CDH23 p.Phe1012Ser

c.3035T>C · rs774623499 · VCV861497

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2654 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00484%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Usher syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.2654	likely benign
REVEL	0.188	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 0.73, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	20.3	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00484% European (non-Finnish) · 57/1,177,320 alleles

Filtering AF 0.00378% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.00373% 60/1,607,694 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00484%	20,655
Remaining individualsnot grpmax-eligible	0.00161%	62,258
Finnishnot grpmax-eligible	0.00158%	63,426
African / African-American	0.00134%	74,820

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.Phe1012Ser
Coding: c.3035T>C
MANE Select: NM_022124
dbSNP: rs774623499
Type: single nucleotide variant
Location: chr10:71706978 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1012: the cadherin 10 domain

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

Disease context

Usher syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Usher syndrome (Orphanet):

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

Similar variants

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CDH23 p.Pro240Leu Pathogenic ★★★ same condition
CDH23 c.1515-12G>A Uncertain significance ★★★ same condition
CDH23 p.Arg301Gln Uncertain significance ★★★ same condition
CDH23 p.Arg3189Gln Uncertain significance ★★★ ⚠ same condition
CDH23 p.Arg3189Trp 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-phe1012ser (accessed [today's date]).

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