Is DSC2 p.Met786Thr (c.2357T>C) pathogenic?

DSC2 p.Met786Thr (c.2357T>C) is classified Uncertain significance in DSC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-03). AlphaMissense: ambiguous (0.3531); Ultra-rare (popmax 0.0264%, sas); Associated with familial isolated arrhythmogenic right ventricular dysplasia.

What condition is associated with DSC2 p.Met786Thr (c.2357T>C)?

DSC2 p.Met786Thr (c.2357T>C) is associated with familial isolated arrhythmogenic right ventricular dysplasia, cardiomyopathy, arrhythmogenic right ventricular dysplasia 11 (ClinVar).

How common is DSC2 p.Met786Thr (c.2357T>C) in the general population?

DSC2 p.Met786Thr (c.2357T>C) is ultra-rare (popmax 0.0264%, sas) (gnomAD).

What do computational predictors say about DSC2 p.Met786Thr (c.2357T>C)?

AlphaMissense predicts ambiguous (score 0.3531) — an in-silico prediction, not a clinical call.

DSC2 p.Met786Thr

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.2357T>C · rs397517398 · VCV46177

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3531 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0264%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

familial isolated arrhythmogenic right ventricular dysplasia

Computational evidence

Protein change
AlphaMissense	0.3531	ambiguous
REVEL	0.218	benign-leaning
SaProt	LLR -6.72	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	21.4	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 0.0264% South Asian · 24/91,078 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.00173% 28/1,613,872 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0264%	3,795
European (non-Finnish)	0.000339%	294,999

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.Met786Thr
Coding: c.2357T>C
MANE Select: NM_024422
dbSNP: rs397517398
Type: single nucleotide variant
Location: chr18:31069045 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 786: 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

Also linked: cardiomyopathy arrhythmogenic right ventricular dysplasia 11

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

DSC2 p.Met786Val Uncertain significance ★ ⚠ same residue
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
DSC2 p.Glu593Ter 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-met786thr (accessed [today's date]).

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