Is CDH6 p.Val123Ile (c.367G>A) pathogenic?

CDH6 p.Val123Ile (c.367G>A) is classified Uncertain significance in CDH6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-11). AlphaMissense: likely benign (0.0659); Ultra-rare (popmax 0.0417%, sas).

How common is CDH6 p.Val123Ile (c.367G>A) in the general population?

CDH6 p.Val123Ile (c.367G>A) is ultra-rare (popmax 0.0417%, sas) (gnomAD).

What do computational predictors say about CDH6 p.Val123Ile (c.367G>A)?

AlphaMissense predicts likely benign (score 0.0659) — an in-silico prediction, not a clinical call.

CDH6 p.Val123Ile

c.367G>A · rs201394958 · VCV2388214

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0659 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0417%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0659	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -6.53	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 5.2	GERP 2, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 50 kb · p 7.7e-20 · regional, not allelic
Overall
CADD	19.34	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 0.0417% South Asian · 38/91,040 alleles

Filtering AF 0.0312% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0276%

Overall 0.0143% 230/1,613,812 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0417%	2,396
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.016%	6,250
European (non-Finnish)	0.0143%	6,982
Admixed American	0.00834%	11,994
African / African-American	0.00534%	18,740
Finnishnot grpmax-eligible	0.00312%	32,001

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: CDH6
Protein: p.Val123Ile
Coding: c.367G>A
MANE Select: NM_004932
dbSNP: rs201394958
Type: single nucleotide variant
Location: chr5:31294100 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 78.67 · 1 PDB
Residue 123: the cadherin 1 domain

Full CDH6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH6 p.Ala130Val Uncertain significance ★ ⚠ same type
CDH6 p.Ala489Ser Uncertain significance ★ ⚠ same type
CDH6 p.Ala634Gly Uncertain significance ★ ⚠ same type
CDH6 p.Ala671Ser Uncertain significance ★ ⚠ same type
CDH6 p.Ala706Val Uncertain significance ★ ⚠ same type
CDH6 p.Ala729Val Uncertain significance ★ ⚠ same type
CDH6 p.Ala739Val Uncertain significance ★ ⚠ same type
CDH6 p.Arg115Lys 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/cdh6-p-val123ile (accessed [today's date]).

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