Is CDH9 p.Phe495Leu (c.1483T>C) pathogenic?

CDH9 p.Phe495Leu (c.1483T>C) is classified Uncertain significance in CDH9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-28). AlphaMissense: likely pathogenic (0.8842); Very rare (popmax 0.00206%, nfe).

How common is CDH9 p.Phe495Leu (c.1483T>C) in the general population?

CDH9 p.Phe495Leu (c.1483T>C) is very rare (popmax 0.00206%, nfe) (gnomAD).

What do computational predictors say about CDH9 p.Phe495Leu (c.1483T>C)?

AlphaMissense predicts likely pathogenic (score 0.8842) — an in-silico prediction, not a clinical call.

CDH9 p.Phe495Leu

c.1483T>C · rs147443121 · VCV2525243

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8842 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00206%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8842	likely pathogenic
REVEL	0.443	indeterminate
SaProt	LLR -9.71	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 107 kb · p 0.00043 · regional, not allelic
Overall
CADD	24.9	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 0.00206% European (non-Finnish) · 24/1,166,644 alleles

Filtering AF 0.00139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00117%

Overall 0.00163% 26/1,597,604 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00206%	48,610
Remaining individualsnot grpmax-eligible	0.00161%	61,940
African / African-American	0.00134%	74,440

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: CDH9
Protein: p.Phe495Leu
Coding: c.1483T>C
MANE Select: NM_016279
dbSNP: rs147443121
Type: single nucleotide variant
Location: chr5:26889865 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI 0.66 (gnomAD)
Structure: AlphaFold pLDDT 77.60
Residue 495: the cadherin 5 domain

Full CDH9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH9 p.Arg53Cys Uncertain significance ★★ ⚠ same type
CDH9 p.Glu603Gly Benign ★★ ⚠ same type
CDH9 p.Pro486= Benign ★★ same type
CDH9 p.Ala186Thr Uncertain significance ★ ⚠ same type
CDH9 p.Ala412Ser Uncertain significance ★ ⚠ same type
CDH9 p.Ala445Gly Uncertain significance ★ ⚠ same type
CDH9 p.Ala500Glu Uncertain significance ★ ⚠ same type
CDH9 p.Arg137Gln 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/cdh9-p-phe495leu (accessed [today's date]).

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