Is DSC2 p.Ala718Ser (c.2152G>T) pathogenic?

DSC2 p.Ala718Ser (c.2152G>T) is classified Uncertain significance in DSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-15). AlphaMissense: likely benign (0.0966); Very rare (popmax 0.0022%, sas); Associated with cardiomyopathy.

What condition is associated with DSC2 p.Ala718Ser (c.2152G>T)?

DSC2 p.Ala718Ser (c.2152G>T) is associated with cardiomyopathy, familial isolated arrhythmogenic right ventricular dysplasia (ClinVar).

How common is DSC2 p.Ala718Ser (c.2152G>T) in the general population?

DSC2 p.Ala718Ser (c.2152G>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about DSC2 p.Ala718Ser (c.2152G>T)?

AlphaMissense predicts likely benign (score 0.0966) — an in-silico prediction, not a clinical call.

DSC2 p.Ala718Ser

c.2152G>T · rs765017458 · VCV2775173

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0966 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.0966	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -5.36	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 -0.98	GERP -2.7
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	10.95	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 0.0022% South Asian · 2/91,068 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000137% 2/1,461,576 alleles · very rare

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.Ala718Ser
Coding: c.2152G>T
MANE Select: NM_024422
dbSNP: rs765017458
Type: single nucleotide variant
Location: chr18:31070824 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 718: 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

cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial isolated arrhythmogenic right ventricular dysplasia

Similar variants

DSC2 p.Ala718fs Conflicting classifications of pathogenicity ★ same residue
DSC3 p.Thr718Asn Uncertain significance ★ ⚠ same residue
DSC2 c.1077+2T>G Uncertain significance ★★ same condition
DSC2 c.1520+4C>T Uncertain significance ★★ same condition
DSC2 c.1520+6T>C Uncertain significance ★★ same condition
DSC2 c.942+3A>G Uncertain significance ★★ same condition
DSC2 c.942+6A>G Uncertain significance ★★ same condition
DSC2 p.Ala138Ser 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-ala718ser (accessed [today's date]).

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