Is CDH6 p.Val373Met (c.1117G>A) pathogenic?

CDH6 p.Val373Met (c.1117G>A) is classified Likely benign in CDH6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-07). AlphaMissense: likely benign (0.0714); Very rare (popmax 0.00223%, eas).

How common is CDH6 p.Val373Met (c.1117G>A) in the general population?

CDH6 p.Val373Met (c.1117G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CDH6 p.Val373Met (c.1117G>A)?

AlphaMissense predicts likely benign (score 0.0714) — an in-silico prediction, not a clinical call.

CDH6 p.Val373Met

c.1117G>A · VCV3830211

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0714 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0714	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -7.56	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 0.3	GERP 0.3
Regional constraint	o/e 0.65	unconstrained · MANE · 50 kb · p 7.7e-20 · regional, not allelic
Overall
CADD	12.95	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 0.00223% East Asian · 1/44,862 alleles

Overall 0.000137% 2/1,461,878 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,862
European (non-Finnish)	8.47e-05%	1,180,030

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.Val373Met
Coding: c.1117G>A
MANE Select: NM_004932
Type: single nucleotide variant
Location: chr5:31305291 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 78.67 · 1 PDB
Residue 373: the cadherin 3 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-val373met (accessed [today's date]).

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