Is DSC2 p.Ile776Val (c.2326A>G) pathogenic?

DSC2 p.Ile776Val (c.2326A>G) is classified Benign in DSC2 (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0608); Common (popmax 40.5%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with DSC2 p.Ile776Val (c.2326A>G)?

DSC2 p.Ile776Val (c.2326A>G) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 11 (ClinVar).

What do computational predictors say about DSC2 p.Ile776Val (c.2326A>G)?

AlphaMissense predicts likely benign (score 0.0608) — an in-silico prediction, not a clinical call.

DSC2 p.Ile776Val

Q: How common is DSC2 p.Ile776Val (c.2326A>G) in the general population?

DSC2 p.Ile776Val (c.2326A>G) is common (popmax 40.5%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2326A>G · rs1893963 · VCV46178

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

AlphaMissense

likely benign

0.0608 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 40.5%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0608	likely benign
REVEL	0.105	moderately benign-leaning
SaProt	LLR -5.07	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 0.13	GERP -0.72, phastCons 0.001
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	0.19	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 40.5% African / African-American · 30,305/74,892 alleles

Filtering AF 40.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 39.9%

Overall 10.3% 166,579/1,613,930 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	40.5%	2
Admixed American	17%	6
Amishnot grpmax-eligible	12.7%	8
Remaining individualsnot grpmax-eligible	10.4%	10
Ashkenazi Jewishnot grpmax-eligible	10.1%	10
Middle Eastern	9.95%	10
East Asian	9.32%	11
European (non-Finnish)	8.64%	12
South Asian	6.62%	15
Finnishnot grpmax-eligible	5.87%	17

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.Ile776Val
Coding: c.2326A>G
MANE Select: NM_024422
dbSNP: rs1893963
Type: single nucleotide variant
Location: chr18:31069076 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 776: a UniProt-annotated variant site (in arvd11; likely pathogenic; mislocalization of dsc2 to the cytoplasm within intercalated disks of the heart); a UniProt-annotated variant site (in)

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.Ile776Met 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
DSC2 p.Glu127Ter Pathogenic/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/dsc2-p-ile776val (accessed [today's date]).

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