Is DSG2 p.Pro123Ser (c.367C>T) pathogenic?

DSG2 p.Pro123Ser (c.367C>T) is classified Uncertain significance in DSG2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-04). AlphaMissense: likely benign (0.2057); Very rare (popmax 0.000424%, nfe); Associated with cardiomyopathy.

How common is DSG2 p.Pro123Ser (c.367C>T) in the general population?

DSG2 p.Pro123Ser (c.367C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about DSG2 p.Pro123Ser (c.367C>T)?

AlphaMissense predicts likely benign (score 0.2057) — an in-silico prediction, not a clinical call.

DSG2 p.Pro123Ser

Q: What condition is associated with DSG2 p.Pro123Ser (c.367C>T)?

DSG2 p.Pro123Ser (c.367C>T) is associated with cardiomyopathy, arrhythmogenic right ventricular dysplasia 10, arrhythmogenic right ventricular cardiomyopathy (ClinVar).

c.367C>T · rs2073124113 · VCV921626

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2057 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.2057	likely benign
REVEL	0.239	benign-leaning
SaProt	LLR -8.96	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 5.9	phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 48 kb · p 0.014 · regional, not allelic
Overall
CADD	23.7	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 0.000424% European (non-Finnish) · 5/1,179,834 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,350 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: DSG2
Protein: p.Pro123Ser
Coding: c.367C>T
MANE Select: NM_001943
dbSNP: rs2073124113
Type: single nucleotide variant
Location: chr18:31520953 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 123: the cadherin 1 domain; a β-strand

Full DSG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: arrhythmogenic right ventricular dysplasia 10 arrhythmogenic right ventricular cardiomyopathy

Similar variants

DSG2 p.Pro123Arg Uncertain significance ★★ ⚠ same residue
DSG2 p.Pro123= Likely benign ★★ same residue
DSG2 p.Pro123Leu Uncertain significance ★ ⚠ same residue
DSG2 c.1423+1G>T Likely pathogenic ★★ same condition
DSG2 c.1424-1G>A Likely pathogenic ★★ same condition
DSG2 c.523+1G>T Pathogenic/Likely pathogenic ★★ same condition
DSG2 c.690+1G>A Pathogenic ★★ same condition
DSG2 c.81+1G>T Likely pathogenic ★★ 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/dsg2-p-pro123ser (accessed [today's date]).

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