Is CDH3 p.Ala40fs (c.118dup) pathogenic?

CDH3 p.Ala40fs (c.118dup) is classified Pathogenic in CDH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-24). Very rare (popmax 0.000523%, nfe).

How common is CDH3 p.Ala40fs (c.118dup) in the general population?

CDH3 p.Ala40fs (c.118dup) is very rare (popmax 0.000523%, nfe) (gnomAD).

CDH3 p.Ala40fs

c.118dup · rs1208055411 · VCV1457451

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000523%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.9	GERP 1.3, phastCons 1
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000523% European (non-Finnish) · 6/1,146,516 alleles

Filtering AF 0.000188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000124%

Overall 0.000388% 6/1,545,698 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: CDH3
Protein: p.Ala40fs
Coding: c.118dup
MANE Select: NM_001793
dbSNP: rs1208055411
Type: Duplication
Location: chr16:68645706 (GRCh38)
Gene constraint: LOEUF 0.823 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.71 · 19 PDB

Full CDH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH3 p.Ala40Glu Uncertain significance ★★ ⚠ same residue
CDH3 p.Asp613fs Pathogenic ★★ same type
CDH3 c.2280+1dup Likely pathogenic ★ same type
CDH3 p.Leu687fs Pathogenic ★ same type
CDH3 p.Thr310fs Pathogenic ★ same type
CDH3 p.Thr770fs Uncertain significance ★ same type
CDH3 c.247-194dup Likely benign ★ same type
CDH3 p.Ser223fs Pathogenic 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/cdh3-p-ala40fs (accessed [today's date]).

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