Is CDH4 p.Arg118Gln (c.353G>A) pathogenic?

CDH4 p.Arg118Gln (c.353G>A) is classified Uncertain significance in CDH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-04). AlphaMissense: likely benign (0.0838); Ultra-rare (popmax 0.028%, afr).

How common is CDH4 p.Arg118Gln (c.353G>A) in the general population?

CDH4 p.Arg118Gln (c.353G>A) is ultra-rare (popmax 0.028%, afr) (gnomAD).

What do computational predictors say about CDH4 p.Arg118Gln (c.353G>A)?

AlphaMissense predicts likely benign (score 0.0838) — an in-silico prediction, not a clinical call.

CDH4 p.Arg118Gln

c.353G>A · rs373320390 · VCV3141283

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0838 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.028%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0838	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -6.70	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 7.3	GERP 1.5, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 521 kb · p 0.43 · regional, not allelic
Overall
CADD	22.8	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 0.028% African / African-American · 21/74,904 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.00248% 40/1,609,800 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.028%	3,567
Remaining individualsnot grpmax-eligible	0.00321%	31,134
Admixed American	0.00168%	59,584
Finnishnot grpmax-eligible	0.00158%	63,224
European (non-Finnish)	0.00119%	84,181
South Asian	0.00111%	90,048

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.Arg118Gln
Coding: c.353G>A
MANE Select: NM_001794
dbSNP: rs373320390
Type: single nucleotide variant
Location: chr20:61743746 (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.Arg118Leu Uncertain significance ★ ⚠ same residue
CDH4 p.Arg118Trp Uncertain significance ★ ⚠ same residue
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

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-arg118gln (accessed [today's date]).

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