Is DSG2 p.Ala186Val (c.557C>T) pathogenic?

DSG2 p.Ala186Val (c.557C>T) is classified Uncertain significance in DSG2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-30). AlphaMissense: ambiguous (0.3679); Very rare (popmax 0.00017%, nfe); Associated with cardiomyopathy.

What condition is associated with DSG2 p.Ala186Val (c.557C>T)?

DSG2 p.Ala186Val (c.557C>T) is associated with cardiomyopathy (ClinVar).

How common is DSG2 p.Ala186Val (c.557C>T) in the general population?

DSG2 p.Ala186Val (c.557C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about DSG2 p.Ala186Val (c.557C>T)?

AlphaMissense predicts ambiguous (score 0.3679) — an in-silico prediction, not a clinical call.

DSG2 p.Ala186Val

c.557C>T · rs2510911574 · VCV3221945

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3679 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.3679	ambiguous
REVEL	0.469	indeterminate
SaProt	LLR -10.71	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 48 kb · p 0.014 · regional, not allelic
Overall
CADD	26.4	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

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,770 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,492 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.Ala186Val
Coding: c.557C>T
MANE Select: NM_001943
dbSNP: rs2510911574
Type: single nucleotide variant
Location: chr18:31522116 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 186: the cadherin 2 domain

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

Similar variants

DSG2 p.Ala186= Likely benign ★★ same residue
DSG2 p.Arg46Gln Pathogenic/Likely pathogenic ★★ same condition
DSG2 p.Arg46Trp Pathogenic/Likely pathogenic ★★ same condition
DSG2 p.Tyr783Ter Pathogenic/Likely pathogenic ★★ same condition
DSG2 c.1014+5G>T Uncertain significance ★★ same condition
DSG2 c.216+3A>C Uncertain significance ★★ same condition
DSG2 c.45+5G>C Uncertain significance ★★ same condition
DSG2 c.46-14A>G 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/dsg2-p-ala186val (accessed [today's date]).

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