Is CDH2 p.Arg749Gln (c.2246G>A) pathogenic?

CDH2 p.Arg749Gln (c.2246G>A) is classified Conflicting classifications of pathogenicity in CDH2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-03). AlphaMissense: ambiguous (0.3469); Ultra-rare (popmax 0.0223%, eas); Associated with Inborn genetic diseases.

What condition is associated with CDH2 p.Arg749Gln (c.2246G>A)?

CDH2 p.Arg749Gln (c.2246G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CDH2 p.Arg749Gln (c.2246G>A) in the general population?

CDH2 p.Arg749Gln (c.2246G>A) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about CDH2 p.Arg749Gln (c.2246G>A)?

AlphaMissense predicts ambiguous (score 0.3469) — an in-silico prediction, not a clinical call.

CDH2 p.Arg749Gln

c.2246G>A · rs373060189 · VCV2074947

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3469 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3469	ambiguous
REVEL	0.805	moderately pathogenic-leaning
SaProt	LLR -7.92	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 27 kb · p 4e-09 · regional, not allelic
Overall
CADD	32.0	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 0.0223% East Asian · 10/44,846 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00917%

Overall 0.00198% 32/1,612,354 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,485
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,390
African / African-American	0.00267%	37,415
Remaining individualsnot grpmax-eligible	0.0016%	62,404
European (non-Finnish)	0.00119%	84,208
South Asian	0.0011%	90,932

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.Arg749Gln
Coding: c.2246G>A
MANE Select: NM_001792
dbSNP: rs373060189
Type: single nucleotide variant
Location: chr18:27983047 (GRCh38)
Gene constraint: LOEUF 0.336 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.68

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDH2 p.Arg749Trp Uncertain significance ★★ ⚠ same residue
CDH2 p.Arg749= Likely benign ★★ same residue
CDH2 p.Ala21Val Uncertain significance ★★ ⚠ same condition
CDH2 p.Ala294Gly Uncertain significance ★★ ⚠ same condition
CDH2 p.Ala299Thr Uncertain significance ★★ ⚠ same condition
CDH2 p.Ala415Ser Uncertain significance ★★ ⚠ same condition
CDH2 p.Ala418Ser Uncertain significance ★★ ⚠ same condition
CDH2 p.Ala418Thr Uncertain significance ★★ ⚠ same condition

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-arg749gln (accessed [today's date]).

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