Is CDH9 p.Leu688Phe (c.2062C>T) pathogenic?

CDH9 p.Leu688Phe (c.2062C>T) is classified Uncertain significance in CDH9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-02). AlphaMissense: likely benign (0.1207); Ultra-rare (popmax 0.0174%, afr).

How common is CDH9 p.Leu688Phe (c.2062C>T) in the general population?

CDH9 p.Leu688Phe (c.2062C>T) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

What do computational predictors say about CDH9 p.Leu688Phe (c.2062C>T)?

AlphaMissense predicts likely benign (score 0.1207) — an in-silico prediction, not a clinical call.

CDH9 p.Leu688Phe

c.2062C>T · VCV3489035

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1207 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1207	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -7.35	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.36, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 107 kb · p 0.00043 · regional, not allelic
Overall
CADD	17.15	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0174% African / African-American · 13/74,846 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.000992% 16/1,613,486 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,757
Remaining individualsnot grpmax-eligible	0.0032%	31,237
East Asian	0.00223%	44,882

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.Leu688Phe
Coding: c.2062C>T
MANE Select: NM_016279
Type: single nucleotide variant
Location: chr5:26881444 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI 0.66 (gnomAD)
Structure: AlphaFold pLDDT 77.60

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-leu688phe (accessed [today's date]).

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