Is CDH2 p.Ser131Pro (c.391T>C) pathogenic?

CDH2 p.Ser131Pro (c.391T>C) is classified Uncertain significance in CDH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-10). AlphaMissense: likely benign (0.059); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with CDH2 p.Ser131Pro (c.391T>C)?

CDH2 p.Ser131Pro (c.391T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CDH2 p.Ser131Pro (c.391T>C) in the general population?

CDH2 p.Ser131Pro (c.391T>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CDH2 p.Ser131Pro (c.391T>C)?

AlphaMissense predicts likely benign (score 0.059) — an in-silico prediction, not a clinical call.

CDH2 p.Ser131Pro

c.391T>C · rs183606230 · VCV1421422

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.059 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.059	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -5.90	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 0.27	GERP -3.5, phastCons 0.001
Regional constraint	o/e 0.90	unconstrained · MANE · 165 kb · p 0.17 · regional, not allelic
Overall
CADD	10.7	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 0.0165% Middle Eastern · 1/6,056 alleles

Filtering AF 0.00816% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00112% 18/1,611,800 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,056
African / African-American	0.0147%	6,809
Remaining individualsnot grpmax-eligible	0.00961%	10,408

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.Ser131Pro
Coding: c.391T>C
MANE Select: NM_001792
dbSNP: rs183606230
Type: single nucleotide variant
Location: chr18:28013691 (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.Ser131Leu Uncertain significance ★★ ⚠ 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-ser131pro (accessed [today's date]).

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