Is CDH2 p.Ala25Thr (c.73G>A) pathogenic?

CDH2 p.Ala25Thr (c.73G>A) is classified Uncertain significance in CDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-09). AlphaMissense: likely benign (0.0964); Very rare (popmax 6.89e-05%).

How common is CDH2 p.Ala25Thr (c.73G>A) in the general population?

CDH2 p.Ala25Thr (c.73G>A) is very rare (popmax 6.89e-05%) (gnomAD).

What do computational predictors say about CDH2 p.Ala25Thr (c.73G>A)?

AlphaMissense predicts likely benign (score 0.0964) — an in-silico prediction, not a clinical call.

CDH2 p.Ala25Thr

c.73G>A · rs2510778357 · VCV2820342

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0964 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.89e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0964	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -7.37	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 2.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 165 kb · p 0.17 · regional, not allelic
Overall
CADD	19.46	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 6.89e-05%

Overall 6.89e-05% 1/1,451,226 alleles · very rare

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.Ala25Thr
Coding: c.73G>A
MANE Select: NM_001792
dbSNP: rs2510778357
Type: single nucleotide variant
Location: chr18:28147772 (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

Similar variants

CDH2 p.Ala25Ser Uncertain significance ★ ⚠ same residue
CDH2 p.Ala25= 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

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-ala25thr (accessed [today's date]).

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