Is DSC2 p.Ala28Ser (c.82G>T) pathogenic?

DSC2 p.Ala28Ser (c.82G>T) is classified Conflicting classifications of pathogenicity in DSC2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-02). AlphaMissense: likely benign (0.0795); Ultra-rare (popmax 0.0354%, afr); Associated with Cardiovascular phenotype.

What condition is associated with DSC2 p.Ala28Ser (c.82G>T)?

DSC2 p.Ala28Ser (c.82G>T) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 11 (ClinVar).

How common is DSC2 p.Ala28Ser (c.82G>T) in the general population?

DSC2 p.Ala28Ser (c.82G>T) is ultra-rare (popmax 0.0354%, afr) (gnomAD).

What do computational predictors say about DSC2 p.Ala28Ser (c.82G>T)?

AlphaMissense predicts likely benign (score 0.0795) — an in-silico prediction, not a clinical call.

DSC2 p.Ala28Ser

c.82G>T · rs139979318 · VCV234988

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0795 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0354%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0795	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -4.95	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 -0.26	GERP 0.28, phastCons 0.007
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	6.992	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 0.0354% African / African-American · 26/73,490 alleles

Filtering AF 0.0247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0212%

Overall 0.00196% 31/1,583,336 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0354%	2,827
Remaining individualsnot grpmax-eligible	0.00329%	30,385
Admixed American	0.00169%	59,046
South Asian	0.00113%	88,636
European (non-Finnish)	8.61e-05%	1,161,406

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.Ala28Ser
Coding: c.82G>T
MANE Select: NM_024422
dbSNP: rs139979318
Type: single nucleotide variant
Location: chr18:31093631 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB

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 dilated cardiomyopathy familial isolated arrhythmogenic right ventricular dysplasia

Similar variants

DSC2 p.Ala28Val Uncertain significance ★ ⚠ same residue
DSC3 p.Ala28Asp Benign ★★ 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-ala28ser (accessed [today's date]).

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