Is DSC2 p.Glu245Ala (c.734A>C) pathogenic?

DSC2 p.Glu245Ala (c.734A>C) is classified Conflicting classifications of pathogenicity in DSC2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-06-12). AlphaMissense: likely benign (0.1502); Ultra-rare (popmax 0.036%, afr); Associated with Cardiovascular phenotype.

What condition is associated with DSC2 p.Glu245Ala (c.734A>C)?

DSC2 p.Glu245Ala (c.734A>C) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 11 (ClinVar).

How common is DSC2 p.Glu245Ala (c.734A>C) in the general population?

DSC2 p.Glu245Ala (c.734A>C) is ultra-rare (popmax 0.036%, afr) (gnomAD).

What do computational predictors say about DSC2 p.Glu245Ala (c.734A>C)?

AlphaMissense predicts likely benign (score 0.1502) — an in-silico prediction, not a clinical call.

DSC2 p.Glu245Ala

c.734A>C · rs373201722 · VCV191624

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1502 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.036%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1502	likely benign
REVEL	0.218	benign-leaning
SaProt	LLR -8.82	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 6.1	GERP 2, phastCons 0.99
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	20.7	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 0.036% African / African-American · 27/74,918 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.00205% 33/1,613,540 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.036%	2,775
Remaining individualsnot grpmax-eligible	0.0032%	31,230
Admixed American	0.00167%	60,002
European (non-Finnish)	0.000254%	393,294

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: DSC2
Protein: p.Glu245Ala
Coding: c.734A>C
MANE Select: NM_024422
dbSNP: rs373201722
Type: single nucleotide variant
Location: chr18:31087710 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 245: the cadherin 2 domain

Full DSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: cardiomyopathy arrhythmogenic right ventricular dysplasia 11 familial isolated arrhythmogenic right ventricular dysplasia

Similar variants

DSC2 p.Glu245Gly Uncertain significance ★★ ⚠ same residue
DSC3 p.Glu245Lys Uncertain significance ★ ⚠ same residue
DSC2 c.1521-1G>A Likely pathogenic ★★ same condition
DSC2 c.1664-1G>A Likely pathogenic ★★ same condition
DSC2 c.354+2T>A Likely pathogenic ★★ same condition
DSC2 c.355-1G>A Likely pathogenic ★★ same condition
DSC2 p.Gln554Ter Pathogenic ★★ same condition
DSC2 p.Gln620Ter 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/dsc2-p-glu245ala (accessed [today's date]).

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