Is CDH4 p.Pro594= (c.1782G>A) pathogenic?

CDH4 p.Pro594= (c.1782G>A) is classified Likely benign in CDH4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-03). Very rare (popmax 0.00267%, afr); Associated with CDH4-related disorder.

What condition is associated with CDH4 p.Pro594= (c.1782G>A)?

CDH4 p.Pro594= (c.1782G>A) is associated with CDH4-related disorder (ClinVar).

How common is CDH4 p.Pro594= (c.1782G>A) in the general population?

CDH4 p.Pro594= (c.1782G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

CDH4 p.Pro594=

c.1782G>A · rs767997015 · VCV3046867

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

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	0.044	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,914 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000937% 15/1,600,568 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,457
Admixed American	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,376
South Asian	0.0011%	91,092
European (non-Finnish)	0.000848%	117,978

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.Pro594=
Coding: c.1782G>A
MANE Select: NM_001794
dbSNP: rs767997015
Type: single nucleotide variant
Location: chr20:61928200 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.54 (gnomAD)
Structure: AlphaFold pLDDT 79.02
Residue 594: the cadherin 4 domain

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

Disease context

CDH4-related disorder

Similar variants

CDH4 p.Pro594Leu Uncertain significance ★ ⚠ same residue
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

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-pro594 (accessed [today's date]).

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