Is CDH2 p.Pro449Thr (c.1345C>A) pathogenic?

CDH2 p.Pro449Thr (c.1345C>A) is classified Uncertain significance in CDH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-13). AlphaMissense: likely benign (0.25); Very rare (popmax 0.00402%, afr); Associated with Inborn genetic diseases.

What condition is associated with CDH2 p.Pro449Thr (c.1345C>A)?

CDH2 p.Pro449Thr (c.1345C>A) is associated with Inborn genetic diseases (ClinVar).

How common is CDH2 p.Pro449Thr (c.1345C>A) in the general population?

CDH2 p.Pro449Thr (c.1345C>A) is very rare (popmax 0.00402%, afr) (gnomAD).

What do computational predictors say about CDH2 p.Pro449Thr (c.1345C>A)?

AlphaMissense predicts likely benign (score 0.25) — an in-silico prediction, not a clinical call.

CDH2 p.Pro449Thr

c.1345C>A · rs759436092 · VCV1770455

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.25 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00402%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.25	likely benign
REVEL	0.347	indeterminate
SaProt	LLR -9.04	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 27 kb · p 4e-09 · regional, not allelic
Overall
CADD	25.5	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 0.00402% African / African-American · 3/74,560 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000496%

Overall 0.000187% 3/1,604,820 alleles · very rare exomes 0/1,452,668 · genomes 3/152,152 · joint denominator

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.Pro449Thr
Coding: c.1345C>A
MANE Select: NM_001792
dbSNP: rs759436092
Type: single nucleotide variant
Location: chr18:27990350 (GRCh38)
Gene constraint: LOEUF 0.336 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.68
Residue 449: the cadherin 3 domain

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.Pro449= 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
CDH2 p.Ala610Thr 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-pro449thr (accessed [today's date]).

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