Is CDH9 p.Val235Ala (c.704T>C) pathogenic?

CDH9 p.Val235Ala (c.704T>C) is classified Uncertain significance in CDH9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-20). AlphaMissense: likely pathogenic (0.5981); Very rare (popmax 0.0011%, sas).

How common is CDH9 p.Val235Ala (c.704T>C) in the general population?

CDH9 p.Val235Ala (c.704T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CDH9 p.Val235Ala (c.704T>C)?

AlphaMissense predicts likely pathogenic (score 0.5981) — an in-silico prediction, not a clinical call.

CDH9 p.Val235Ala

c.704T>C · rs2477697301 · VCV2476781

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5981 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5981	likely pathogenic
REVEL	0.335	indeterminate
SaProt	LLR -11.52	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 107 kb · p 0.00043 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0011% South Asian · 1/91,078 alleles

Overall 6.84e-05% 1/1,461,564 alleles · very rare

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.Val235Ala
Coding: c.704T>C
MANE Select: NM_016279
dbSNP: rs2477697301
Type: single nucleotide variant
Location: chr5:26906066 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI 0.66 (gnomAD)
Structure: AlphaFold pLDDT 77.60
Residue 235: the cadherin 2 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-val235ala (accessed [today's date]).

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