Is DSC2 p.Ala753Val (c.2258C>T) pathogenic?

DSC2 p.Ala753Val (c.2258C>T) is classified Uncertain significance in DSC2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-10). AlphaMissense: likely benign (0.0949); Very rare (popmax 0.00446%, eas); Associated with arrhythmogenic right ventricular dysplasia 11.

What condition is associated with DSC2 p.Ala753Val (c.2258C>T)?

DSC2 p.Ala753Val (c.2258C>T) is associated with arrhythmogenic right ventricular dysplasia 11, cardiomyopathy, familial isolated arrhythmogenic right ventricular dysplasia (ClinVar).

How common is DSC2 p.Ala753Val (c.2258C>T) in the general population?

DSC2 p.Ala753Val (c.2258C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about DSC2 p.Ala753Val (c.2258C>T)?

AlphaMissense predicts likely benign (score 0.0949) — an in-silico prediction, not a clinical call.

DSC2 p.Ala753Val

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.2258C>T · rs1217851416 · VCV536263

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0949 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arrhythmogenic right ventricular dysplasia 11

Computational evidence

Protein change
AlphaMissense	0.0949	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -5.23	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 3.9	GERP 0.32, phastCons 0.77
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	12.45	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00446% East Asian · 2/44,880 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000929% 15/1,613,938 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,440
South Asian	0.0022%	45,542
African / African-American	0.00134%	74,892
European (non-Finnish)	0.000847%	118,000

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.Ala753Val
Coding: c.2258C>T
MANE Select: NM_024422
dbSNP: rs1217851416
Type: single nucleotide variant
Location: chr18:31069144 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 753: 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

arrhythmogenic right ventricular dysplasia 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy familial isolated arrhythmogenic right ventricular dysplasia

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

DSC2 p.Ala753= Likely benign ★★ same residue
DSC3 p.Thr753Ser 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

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-ala753val (accessed [today's date]).

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