Is CDHR3 p.Pro355Leu (c.1064C>T) pathogenic?

CDHR3 p.Pro355Leu (c.1064C>T) is classified Uncertain significance in CDHR3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2013-02-01). AlphaMissense: likely benign (0.1095); Very rare (popmax 0.00693%, amr); Associated with Susceptibility to nonsyndromic otitis media.

What condition is associated with CDHR3 p.Pro355Leu (c.1064C>T)?

CDHR3 p.Pro355Leu (c.1064C>T) is associated with Susceptibility to nonsyndromic otitis media (ClinVar).

How common is CDHR3 p.Pro355Leu (c.1064C>T) in the general population?

CDHR3 p.Pro355Leu (c.1064C>T) is very rare (popmax 0.00693%, amr) (gnomAD).

What do computational predictors say about CDHR3 p.Pro355Leu (c.1064C>T)?

AlphaMissense predicts likely benign (score 0.1095) — an in-silico prediction, not a clinical call.

CDHR3 p.Pro355Leu

c.1064C>T · rs202204966 · VCV1294430

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1095 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00693%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Susceptibility to nonsyndromic otitis media

Computational evidence

Protein change
AlphaMissense	0.1095	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -10.98	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 2.8, phastCons 0.007
Regional constraint	o/e 1.00	unconstrained · MANE · 69 kb · p 0.92 · regional, not allelic
Overall
CADD	17.16	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 0.00693% Admixed American · 4/57,742 alleles

Filtering AF 0.00232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00139%

Overall 0.00524% 84/1,603,242 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0941%	1,063
Admixed Americangrpmax	0.00693%	14,435
Remaining individualsnot grpmax-eligible	0.00484%	20,674
East Asian	0.00224%	44,690
African / African-American	0.00134%	74,410
European (non-Finnish)	0.00128%	78,384

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: CDHR3
Protein: p.Pro355Leu
Coding: c.1064C>T
MANE Select: NM_152750
dbSNP: rs202204966
Type: single nucleotide variant
Location: chr7:106012871 (GRCh38)
Gene constraint: LOEUF 1.087 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.08 · 3 PDB
Residue 355: the cadherin 4 domain

Full CDHR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Susceptibility to nonsyndromic otitis media

Similar variants

CDHR3 p.Pro355Ser Uncertain significance ★ ⚠ same residue
CDHR3 p.Pro379Ser Uncertain significance ⚠ same condition
CDHR3 p.Tyr729His Uncertain significance ⚠ same condition
CDHR3 c.1653+3G>A Benign/Likely benign ★★ same type
CDHR3 p.Arg603Cys Likely benign ★★ ⚠ same type
CDHR3 p.Asp337= Benign ★★ same type
CDHR3 p.Gln399= Benign ★★ same type
CDHR3 p.Ala148Ser Uncertain significance ★ ⚠ same type

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/cdhr3-p-pro355leu (accessed [today's date]).

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