Is CDH2 p.Leu8Pro (c.23T>C) pathogenic?

CDH2 p.Leu8Pro (c.23T>C) is classified Conflicting classifications of pathogenicity in CDH2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-01-11). AlphaMissense: likely benign (0.0726); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CDH2 p.Leu8Pro (c.23T>C)?

CDH2 p.Leu8Pro (c.23T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CDH2 p.Leu8Pro (c.23T>C) in the general population?

CDH2 p.Leu8Pro (c.23T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDH2 p.Leu8Pro (c.23T>C)?

AlphaMissense predicts likely benign (score 0.0726) — an in-silico prediction, not a clinical call.

CDH2 p.Leu8Pro

c.23T>C · rs1293733346 · VCV1790721

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0726 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,481,274)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0726	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -8.59	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 5	GERP 0.78, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 165 kb · p 0.17 · regional, not allelic
Overall
CADD	20.9	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

No allele count reported in gnomAD v4.1 (AN 1,481,274). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CDH2
Protein: p.Leu8Pro
Coding: c.23T>C
MANE Select: NM_001792
dbSNP: rs1293733346
Type: single nucleotide variant
Location: chr18:28177000 (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.Leu8Val Uncertain significance ★ ⚠ same residue
CDH2 p.Leu8= 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-leu8pro (accessed [today's date]).

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