Is DSC2 p.Ile577Val (c.1729A>G) pathogenic?

DSC2 p.Ile577Val (c.1729A>G) is classified Conflicting classifications of pathogenicity in DSC2 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-04-28). AlphaMissense: likely benign (0.2498); Ultra-rare (popmax 0.0412%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with DSC2 p.Ile577Val (c.1729A>G)?

DSC2 p.Ile577Val (c.1729A>G) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 11 (ClinVar).

How common is DSC2 p.Ile577Val (c.1729A>G) in the general population?

DSC2 p.Ile577Val (c.1729A>G) is ultra-rare (popmax 0.0412%, nfe) (gnomAD).

What do computational predictors say about DSC2 p.Ile577Val (c.1729A>G)?

AlphaMissense predicts likely benign (score 0.2498) — an in-silico prediction, not a clinical call.

DSC2 p.Ile577Val

c.1729A>G · rs201845641 · VCV46170

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.2498 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0412%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2498	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -7.48	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.2	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	14.86	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 0.0412% European (non-Finnish) · 486/1,179,980 alleles

Filtering AF 0.0381% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0369%

Overall 0.0319% 515/1,613,872 alleles · ultra-rare exomes 480/1,461,756 · genomes 35/152,116 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0412%	2,428
Remaining individualsnot grpmax-eligible	0.016%	6,247
African / African-American	0.0147%	6,810
Finnishnot grpmax-eligible	0.0109%	9,145
Admixed American	0.00167%	59,984

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.Ile577Val
Coding: c.1729A>G
MANE Select: NM_024422
dbSNP: rs201845641
Type: single nucleotide variant
Location: chr18:31074842 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 577: a UniProt-annotated variant site (in arvd11; likely pathogenic; mislocalization of dsc2 to the cytoplasm within intercalated disks of the heart); the cadherin 4 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

Similar variants

DSC2 p.Ile577Met Uncertain significance ★★ same residue
DSC2 p.Ile577Thr Uncertain significance ★★ ⚠ same residue
DSC2 p.Ile577Leu Conflicting classifications of pathogenicity ★ ⚠ 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

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-ile577val (accessed [today's date]).

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