Is CDH4 p.Arg19Gln (c.56G>A) pathogenic?

CDH4 p.Arg19Gln (c.56G>A) is classified Uncertain significance in CDH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: likely benign (0.124); Ultra-rare (popmax 0.0317%, afr).

How common is CDH4 p.Arg19Gln (c.56G>A) in the general population?

CDH4 p.Arg19Gln (c.56G>A) is ultra-rare (popmax 0.0317%, afr) (gnomAD).

What do computational predictors say about CDH4 p.Arg19Gln (c.56G>A)?

AlphaMissense predicts likely benign (score 0.124) — an in-silico prediction, not a clinical call.

CDH4 p.Arg19Gln

c.56G>A · VCV3999031

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.124 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.124	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -6.75	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 6.2	GERP 0.94, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 521 kb · p 0.43 · regional, not allelic
Overall
CADD	19.03	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 0.0317% African / African-American · 20/63,056 alleles

Filtering AF 0.0209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0176%

Overall 0.00183% 22/1,203,828 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0317%	3,153
Remaining individualsnot grpmax-eligible	0.00229%	43,576
European (non-Finnish)	0.000103%	969,772

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.Arg19Gln
Coding: c.56G>A
MANE Select: NM_001794
Type: single nucleotide variant
Location: chr20:61252569 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.54 (gnomAD)
Structure: AlphaFold pLDDT 79.02

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-arg19gln (accessed [today's date]).

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