Is DSC2 p.His604Arg (c.1811A>G) pathogenic?

DSC2 p.His604Arg (c.1811A>G) is classified Conflicting classifications of pathogenicity in DSC2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-17). AlphaMissense: ambiguous (0.4248); Very rare (popmax 0.00223%, eas); Associated with Cardiovascular phenotype.

What condition is associated with DSC2 p.His604Arg (c.1811A>G)?

DSC2 p.His604Arg (c.1811A>G) is associated with Cardiovascular phenotype, arrhythmogenic right ventricular dysplasia 11 (ClinVar).

How common is DSC2 p.His604Arg (c.1811A>G) in the general population?

DSC2 p.His604Arg (c.1811A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about DSC2 p.His604Arg (c.1811A>G)?

AlphaMissense predicts ambiguous (score 0.4248) — an in-silico prediction, not a clinical call.

DSC2 p.His604Arg

c.1811A>G · rs1206662571 · VCV1900619

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4248 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4248	ambiguous
REVEL	0.134	moderately benign-leaning
SaProt	LLR -8.48	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 0.99
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	18.71	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 0.00223% East Asian · 1/44,872 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000496% 8/1,613,938 alleles · very rare exomes 5/1,461,812 · genomes 3/152,126 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00469%	21,342
East Asiangrpmax	0.00223%	44,872
Remaining individualsnot grpmax-eligible	0.0016%	62,480
African / African-American	0.00133%	74,908
European (non-Finnish)	0.000169%	589,998

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.His604Arg
Coding: c.1811A>G
MANE Select: NM_024422
dbSNP: rs1206662571
Type: single nucleotide variant
Location: chr18:31074760 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 604: 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); an α-helix

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: arrhythmogenic right ventricular dysplasia 11

Similar variants

DSC2 p.His604= Likely benign ★★ same residue
DSC2 p.His604Gln Uncertain significance ★ ⚠ same residue
DSC2 p.His604Asn Likely benign ★ 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-his604arg (accessed [today's date]).

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