Is CDH4 p.Arg349Gln (c.1046G>A) pathogenic?

CDH4 p.Arg349Gln (c.1046G>A) is classified Uncertain significance in CDH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-03). AlphaMissense: likely pathogenic (0.6977); Ultra-rare (popmax 0.0164%, mid).

How common is CDH4 p.Arg349Gln (c.1046G>A) in the general population?

CDH4 p.Arg349Gln (c.1046G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CDH4 p.Arg349Gln (c.1046G>A)?

AlphaMissense predicts likely pathogenic (score 0.6977) — an in-silico prediction, not a clinical call.

CDH4 p.Arg349Gln

c.1046G>A · VCV3265308

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6977 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6977	likely pathogenic
REVEL	0.56	indeterminate
SaProt	LLR -14.01	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 160 kb · p 4.6e-12 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00093% 15/1,613,178 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
South Asian	0.00329%	30,354
African / African-American	0.00267%	37,468
East Asian	0.00223%	44,888
European (non-Finnish)	0.000678%	147,486

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.Arg349Gln
Coding: c.1046G>A
MANE Select: NM_001794
Type: single nucleotide variant
Location: chr20:61873896 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.54 (gnomAD)
Structure: AlphaFold pLDDT 79.02
Residue 349: the cadherin 2 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-arg349gln (accessed [today's date]).

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