Is DSC3 p.Tyr609Asp (c.1825T>G) pathogenic?

DSC3 p.Tyr609Asp (c.1825T>G) is classified Uncertain significance in DSC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-21). AlphaMissense: likely benign (0.0769); Very rare (popmax 0.0011%, sas).

How common is DSC3 p.Tyr609Asp (c.1825T>G) in the general population?

DSC3 p.Tyr609Asp (c.1825T>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about DSC3 p.Tyr609Asp (c.1825T>G)?

AlphaMissense predicts likely benign (score 0.0769) — an in-silico prediction, not a clinical call.

DSC3 p.Tyr609Asp

c.1825T>G · rs1410520167 · VCV3085860

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0769 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0769	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -7.35	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 2.7	GERP -3.2, phastCons 1
Overall
CADD	16.34	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 0.0011% South Asian · 1/91,088 alleles

Overall 0.000124% 2/1,613,832 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,030
South Asiangrpmax	0.0011%	91,088

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: DSC3
Protein: p.Tyr609Asp
Coding: c.1825T>G
MANE Select: NM_024422 · reported on NM_001941
dbSNP: rs1410520167
Type: single nucleotide variant
Location: chr18:31006970 (GRCh38)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 609: 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); a β-strand

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

Similar variants

DSC2 p.Asp609Val Uncertain significance ★★ ⚠ same residue
DSC2 p.Asp609His Uncertain significance ★ ⚠ same residue
DSC3 p.Tyr609Cys 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

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-tyr609asp (accessed [today's date]).

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