Is CDH4 p.Pro655= (c.1965G>A) pathogenic?

CDH4 p.Pro655= (c.1965G>A) is classified Benign in CDH4 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2019-06-27). Low-frequency (popmax 2.1%, nfe); Associated with CDH4-related disorder.

What condition is associated with CDH4 p.Pro655= (c.1965G>A)?

CDH4 p.Pro655= (c.1965G>A) is associated with CDH4-related disorder (ClinVar).

How common is CDH4 p.Pro655= (c.1965G>A) in the general population?

CDH4 p.Pro655= (c.1965G>A) is low-frequency (popmax 2.1%, nfe) (gnomAD).

CDH4 p.Pro655=

c.1965G>A · rs142995081 · VCV3060498

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.1%, nfe)

Conditions

CDH4-related disorder

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 -20	GERP -4.2
Overall
CADD	0.142	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.1% European (non-Finnish) · 24,775/1,179,998 alleles

Filtering AF 2.08% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.07%

Overall 1.68% 27,078/1,611,808 alleles · low-frequency

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	2.1%	48
Remaining individualsnot grpmax-eligible	1.31%	76
Finnishnot grpmax-eligible	0.862%	116
Admixed American	0.608%	164
South Asian	0.322%	311
African / African-American	0.28%	357
Middle Eastern	0.247%	404
Ashkenazi Jewishnot grpmax-eligible	0.223%	448
Amishnot grpmax-eligible	0.11%	912
East Asian	0.00668%	14,961

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: CDH4
Protein: p.Pro655=
Coding: c.1965G>A
MANE Select: NM_001794
dbSNP: rs142995081
Type: single nucleotide variant
Location: chr20:61928383 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.54 (gnomAD)
Structure: AlphaFold pLDDT 79.02
Residue 655: the cadherin 5 domain

Full CDH4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CDH4-related disorder

Similar variants

CDH4 p.Thr396Met Uncertain significance ★★ ⚠ same condition
CDH4 p.Val580Ile Uncertain significance ★★ ⚠ same condition
CDH4 c.169+234620C>T Uncertain significance ★ same condition
CDH4 p.Ile738Leu Uncertain significance ★ ⚠ same condition
CDH4 c.1188+7C>A Likely benign same condition
CDH4 c.1189-9A>G Likely benign same condition
CDH4 c.170-244074G>T Likely benign same condition
CDH4 c.170-244081C>T Likely benign same condition

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/cdh4-p-pro655 (accessed [today's date]).

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