Is CDH2 p.Arg339Gln (c.1016G>A) pathogenic?

CDH2 p.Arg339Gln (c.1016G>A) is classified Uncertain significance in CDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-13). AlphaMissense: likely pathogenic (0.6481); Very rare (popmax 0.00333%, amr).

How common is CDH2 p.Arg339Gln (c.1016G>A) in the general population?

CDH2 p.Arg339Gln (c.1016G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CDH2 p.Arg339Gln (c.1016G>A)?

AlphaMissense predicts likely pathogenic (score 0.6481) — an in-silico prediction, not a clinical call.

CDH2 p.Arg339Gln

c.1016G>A · VCV4781947

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6481 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6481	likely pathogenic
REVEL	0.584	indeterminate
SaProt	LLR -13.81	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 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 27 kb · p 4e-09 · 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 0.00333% Admixed American · 2/59,992 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000548% 8/1,460,680 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,996
African / African-American	0.00133%	74,994
South Asian	0.0011%	90,996
European (non-Finnish)	0.000339%	294,778

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: CDH2
Protein: p.Arg339Gln
Coding: c.1016G>A
MANE Select: NM_001792
Type: single nucleotide variant
Location: chr18:28003001 (GRCh38)
Gene constraint: LOEUF 0.336 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.68
Residue 339: the cadherin 2 domain

Full CDH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH2 p.Arg339= Likely benign ★★ same residue
CDH2 c.1344+1G>A Pathogenic/Likely pathogenic ★★ same type
CDH2 c.702+1G>A Pathogenic/Likely pathogenic ★★ same type
CDH2 p.Tyr676Cys Pathogenic ★★ same type
CDH2 c.61-1G>A Uncertain significance ★★ same type
CDH2 c.848-16T>G Uncertain significance ★★ same type
CDH2 p.Ala106Val Uncertain significance ★★ ⚠ same type
CDH2 p.Ala21Val Uncertain significance ★★ ⚠ 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/cdh2-p-arg339gln (accessed [today's date]).

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