Is DSC3 p.Arg557Ile (c.1670G>T) pathogenic?

DSC3 p.Arg557Ile (c.1670G>T) is classified Uncertain significance in DSC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-26). AlphaMissense: likely benign (0.301); Ultra-rare (popmax 0.0332%, mid).

How common is DSC3 p.Arg557Ile (c.1670G>T) in the general population?

DSC3 p.Arg557Ile (c.1670G>T) is ultra-rare (popmax 0.0332%, mid) (gnomAD).

What do computational predictors say about DSC3 p.Arg557Ile (c.1670G>T)?

AlphaMissense predicts likely benign (score 0.301) — an in-silico prediction, not a clinical call.

DSC3 p.Arg557Ile

c.1670G>T · rs1230194874 · VCV2320379

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.301 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0332%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.301	likely benign
REVEL	0.221	benign-leaning
SaProt	LLR -10.78	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.002	GERP 0.29, phastCons 0.008
Overall
CADD	19.49	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 0.0332% Middle Eastern · 2/6,032 alleles

Filtering AF 0.00584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00243%

Overall 0.000412% 6/1,458,046 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0332%	3,016
Remaining individualsnot grpmax-eligible	0.0016%	62,364
European (non-Finnish)	0.000255%	392,251

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: DSC3
Protein: p.Arg557Ile
Coding: c.1670G>T
MANE Select: NM_024422 · reported on NM_001941
dbSNP: rs1230194874
Type: single nucleotide variant
Location: chr18:31007125 (GRCh38)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 557: a UniProt-annotated variant site (in arvd11; likely pathogenic; mislocalization of dsc2 to the cytoplasm within intercalated disks of the heart); the cadherin 4 domain

Full DSC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DSC2 p.Arg557Gly Uncertain significance ★ ⚠ same residue
DSC2 c.1521-1G>A Likely pathogenic ★★ same type
DSC2 c.1664-1G>A Likely pathogenic ★★ same type
DSC2 c.354+2T>A Likely pathogenic ★★ same type
DSC2 c.355-1G>A Likely pathogenic ★★ same type
DSC2 p.Gln554Ter Pathogenic ★★ same type
DSC2 p.Gln620Ter Pathogenic ★★ same type
DSC2 p.Glu127Ter Pathogenic/Likely pathogenic ★★ same type

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/dsc3-p-arg557ile (accessed [today's date]).

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