Is CDH4 p.Arg418Gln (c.1253G>A) pathogenic?

CDH4 p.Arg418Gln (c.1253G>A) is classified Conflicting classifications of pathogenicity in CDH4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-02-16). AlphaMissense: likely benign (0.1072); Ultra-rare (popmax 0.0517%, amr).

How common is CDH4 p.Arg418Gln (c.1253G>A) in the general population?

CDH4 p.Arg418Gln (c.1253G>A) is ultra-rare (popmax 0.0517%, amr) (gnomAD).

What do computational predictors say about CDH4 p.Arg418Gln (c.1253G>A)?

AlphaMissense predicts likely benign (score 0.1072) — an in-silico prediction, not a clinical call.

CDH4 p.Arg418Gln

c.1253G>A · rs751782763 · VCV2355701

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1072 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0517%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1072	likely benign
REVEL	0.154	moderately benign-leaning
SaProt	LLR -8.16	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 8.3	GERP -3.4, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 160 kb · p 4.6e-12 · regional, not allelic
Overall
CADD	29.3	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 0.0517% Admixed American · 31/60,000 alleles

Filtering AF 0.0374% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0325%

Overall 0.00341% 55/1,613,866 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0517%	1,935
Middle Eastern	0.0493%	2,028
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	0.00153%	65,558
South Asian	0.0011%	91,082

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.Arg418Gln
Coding: c.1253G>A
MANE Select: NM_001794
dbSNP: rs751782763
Type: single nucleotide variant
Location: chr20:61910486 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.54 (gnomAD)
Structure: AlphaFold pLDDT 79.02
Residue 418: the cadherin 3 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-arg418gln (accessed [today's date]).

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