Is CDH4 p.Val580Ile (c.1738G>A) pathogenic?

CDH4 p.Val580Ile (c.1738G>A) is classified Uncertain significance in CDH4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-28). AlphaMissense: likely benign (0.0611); Ultra-rare (popmax 0.0267%, amr); Associated with CDH4-related disorder.

What condition is associated with CDH4 p.Val580Ile (c.1738G>A)?

CDH4 p.Val580Ile (c.1738G>A) is associated with CDH4-related disorder (ClinVar).

How common is CDH4 p.Val580Ile (c.1738G>A) in the general population?

CDH4 p.Val580Ile (c.1738G>A) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about CDH4 p.Val580Ile (c.1738G>A)?

AlphaMissense predicts likely benign (score 0.0611) — an in-silico prediction, not a clinical call.

CDH4 p.Val580Ile

c.1738G>A · rs747641695 · VCV2636013

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0611 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CDH4-related disorder

Computational evidence

Protein change
AlphaMissense	0.0611	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -6.07	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 0.084	GERP -4.2, phastCons 0.001
Regional constraint	o/e 0.77	unconstrained · MANE · 160 kb · p 4.6e-12 · regional, not allelic
Overall
CADD	16.05	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% Admixed American · 16/59,984 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00223% 36/1,613,610 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,749
Remaining individualsnot grpmax-eligible	0.0048%	20,824
East Asian	0.00446%	22,437
Finnishnot grpmax-eligible	0.00313%	31,910
African / African-American	0.00133%	74,920
European (non-Finnish)	0.00102%	98,325

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.Val580Ile
Coding: c.1738G>A
MANE Select: NM_001794
dbSNP: rs747641695
Type: single nucleotide variant
Location: chr20:61924443 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.54 (gnomAD)
Structure: AlphaFold pLDDT 79.02
Residue 580: 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.Val580Leu Uncertain significance ★ ⚠ same residue
CDH4 p.Thr396Met 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-val580ile (accessed [today's date]).

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