Is CDH4 p.Asn557Ser (c.1670A>G) pathogenic?

CDH4 p.Asn557Ser (c.1670A>G) is classified Uncertain significance in CDH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). AlphaMissense: likely benign (0.0866); Very rare (popmax 0.00668%, afr).

How common is CDH4 p.Asn557Ser (c.1670A>G) in the general population?

CDH4 p.Asn557Ser (c.1670A>G) is very rare (popmax 0.00668%, afr) (gnomAD).

What do computational predictors say about CDH4 p.Asn557Ser (c.1670A>G)?

AlphaMissense predicts likely benign (score 0.0866) — an in-silico prediction, not a clinical call.

CDH4 p.Asn557Ser

c.1670A>G · VCV4223923

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0866 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0866	likely benign
REVEL	0.472	indeterminate
SaProt	LLR -10.96	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 160 kb · p 4.6e-12 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% African / African-American · 5/74,890 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.00136% 22/1,613,714 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00668%	14,978
South Asian	0.00329%	30,359
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)	0.0011%	90,766

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.Asn557Ser
Coding: c.1670A>G
MANE Select: NM_001794
Type: single nucleotide variant
Location: chr20:61924375 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.54 (gnomAD)
Structure: AlphaFold pLDDT 79.02
Residue 557: the cadherin 4 domain

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

Similar variants

CDH4 p.Thr396Met Uncertain significance ★★ ⚠ same type
CDH4 p.Val580Ile Uncertain significance ★★ ⚠ same type
CDH4 c.1629-8C>T Benign ★★ same type
CDH4 c.2240-4A>G Benign ★★ same type
CDH4 p.Ala33Thr Benign ★★ same type
CDH4 p.Ala344= Benign/Likely benign ★★ same type
CDH4 p.Asn283= Benign/Likely benign ★★ same type
CDH4 p.Asn450= Benign/Likely benign ★★ 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/cdh4-p-asn557ser (accessed [today's date]).

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