Is DSC2 p.Val666Phe (c.1996G>T) pathogenic?

DSC2 p.Val666Phe (c.1996G>T) is classified Uncertain significance in DSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-15). AlphaMissense: likely pathogenic (0.7748); Absent from gnomAD v4.1; Associated with familial isolated arrhythmogenic right ventricular dysplasia.

What condition is associated with DSC2 p.Val666Phe (c.1996G>T)?

DSC2 p.Val666Phe (c.1996G>T) is associated with familial isolated arrhythmogenic right ventricular dysplasia (ClinVar).

How common is DSC2 p.Val666Phe (c.1996G>T) in the general population?

DSC2 p.Val666Phe (c.1996G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DSC2 p.Val666Phe (c.1996G>T)?

AlphaMissense predicts likely pathogenic (score 0.7748) — an in-silico prediction, not a clinical call.

DSC2 p.Val666Phe

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1996G>T · rs758646191 · VCV3072825

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7748 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial isolated arrhythmogenic right ventricular dysplasia

Computational evidence

Protein change
AlphaMissense	0.7748	likely pathogenic
REVEL	0.482	indeterminate
SaProt	LLR -14.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.9, phastCons 0.99
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DSC2
Protein: p.Val666Phe
Coding: c.1996G>T
MANE Select: NM_024422
dbSNP: rs758646191
Type: single nucleotide variant
Location: chr18:31071734 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 666: the cadherin 5 domain; a UniProt-annotated variant site (in arvd11; likely pathogenic; mislocalization of dsc2 to the cytoplasm within intercalated disks of the heart)

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

Disease context

familial isolated arrhythmogenic right ventricular dysplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

DSC2 p.Val666Ile Uncertain significance ★★ ⚠ same residue
DSC2 c.1077+2T>G Uncertain significance ★★ same condition
DSC2 c.1520+6T>C Uncertain significance ★★ same condition
DSC2 c.942+3A>G Uncertain significance ★★ same condition
DSC2 p.Ala138Ser Uncertain significance ★★ ⚠ same condition
DSC2 p.Ala13Val Uncertain significance ★★ ⚠ same condition
DSC2 p.Ala213Val Uncertain significance ★★ ⚠ same condition
DSC2 p.Ala267Pro 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/dsc2-p-val666phe (accessed [today's date]).

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