Is CDH2 p.Arg697= (c.2091T>C) pathogenic?

CDH2 p.Arg697= (c.2091T>C) is classified Benign in CDH2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 100%, nfe) — too common for a highly-penetrant pathogenic allele.

CDH2 p.Arg697=

Q: How common is CDH2 p.Arg697= (c.2091T>C) in the general population?

CDH2 p.Arg697= (c.2091T>C) is common (popmax 100%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2091T>C · rs1220144 · VCV1600592

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 100%, nfe) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.1	GERP -5.6
Overall
CADD	0.111	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 100% European (non-Finnish) · 1,179,872/1,179,932 alleles

Filtering AF 99.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 99.8%

Overall 99.8% 1,611,326/1,614,058 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	100%	1
Amishnot grpmax-eligible	100%	1
Ashkenazi Jewishnot grpmax-eligible	100%	1
European (non-Finnish)grpmax	100%	1
East Asian	100%	1
South Asian	100%	1
Admixed American	99.9%	1
Middle Eastern	99.8%	1
Remaining individualsnot grpmax-eligible	99.8%	1
African / African-American	96.8%	1

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CDH2
Protein: p.Arg697=
Coding: c.2091T>C
MANE Select: NM_001792
dbSNP: rs1220144
Type: single nucleotide variant
Location: chr18:27985118 (GRCh38)
Gene constraint: LOEUF 0.336 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.68
Residue 697: the cadherin 5 domain

Full CDH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH2 p.Arg697Cys Uncertain significance ★★ ⚠ same residue
CDH2 p.Arg697His Uncertain significance ★ same residue
CDH2 p.Arg697Leu Uncertain significance ★ same residue
CDH2 c.1344+1G>A Pathogenic/Likely pathogenic ★★ same type
CDH2 c.702+1G>A Pathogenic/Likely pathogenic ★★ same type
CDH2 p.Tyr676Cys Pathogenic ★★ same type
CDH2 c.61-1G>A Uncertain significance ★★ same type
CDH2 c.848-16T>G 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/cdh2-p-arg697 (accessed [today's date]).

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