Is DSC2 p.Pro473Ser (c.1417C>T) pathogenic?

DSC2 p.Pro473Ser (c.1417C>T) is classified Uncertain significance in DSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-05). AlphaMissense: ambiguous (0.4316); Ultra-rare (popmax 0.0495%, mid); Associated with cardiomyopathy.

What condition is associated with DSC2 p.Pro473Ser (c.1417C>T)?

DSC2 p.Pro473Ser (c.1417C>T) is associated with cardiomyopathy (ClinVar).

How common is DSC2 p.Pro473Ser (c.1417C>T) in the general population?

DSC2 p.Pro473Ser (c.1417C>T) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about DSC2 p.Pro473Ser (c.1417C>T)?

AlphaMissense predicts ambiguous (score 0.4316) — an in-silico prediction, not a clinical call.

DSC2 p.Pro473Ser

c.1417C>T · rs865914095 · VCV919703

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4316 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.4316	ambiguous
REVEL	0.286	benign-leaning
SaProt	LLR -6.34	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	27.2	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 0.0495% Middle Eastern · 3/6,062 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00718%

Overall 0.000274% 4/1,461,828 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,021
European (non-Finnish)	8.47e-05%	1,180,002

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.Pro473Ser
Coding: c.1417C>T
MANE Select: NM_024422
dbSNP: rs865914095
Type: single nucleotide variant
Location: chr18:31080199 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 473: a β-strand; the cadherin 4 domain

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

Similar variants

DSC2 p.Pro473Leu Uncertain significance ★★ ⚠ same residue
DSC2 c.1077+2T>G Uncertain significance ★★ same condition
DSC2 c.1520+4C>T 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
DSC2 p.Ala213Val Uncertain significance ★★ ⚠ same condition
DSC2 p.Ala23Val 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-pro473ser (accessed [today's date]).

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