Is DSC3 p.Arg7Pro (c.20G>C) pathogenic?

DSC3 p.Arg7Pro (c.20G>C) is classified Uncertain significance in DSC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely benign (0.0843); Ultra-rare (popmax 0.0168%, mid).

How common is DSC3 p.Arg7Pro (c.20G>C) in the general population?

DSC3 p.Arg7Pro (c.20G>C) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

What do computational predictors say about DSC3 p.Arg7Pro (c.20G>C)?

AlphaMissense predicts likely benign (score 0.0843) — an in-silico prediction, not a clinical call.

DSC3 p.Arg7Pro

c.20G>C · VCV4662222

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0843 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0843	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -6.96	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 -5.8	GERP -2.9
Overall
CADD	0.139	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 0.0168% Middle Eastern · 1/5,958 alleles

Filtering AF 0.0015% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00126%

Overall 0.00194% 30/1,549,746 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,958
Admixed American	0.00392%	25,483
Remaining individualsnot grpmax-eligible	0.00333%	30,024
European (non-Finnish)	0.00218%	45,859

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.Arg7Pro
Coding: c.20G>C
MANE Select: NM_024422 · reported on NM_001941
Type: single nucleotide variant
Location: chr18:31042641 (GRCh38)
Structure: AlphaFold pLDDT 77.26 · 3 PDB

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

Similar variants

DSC2 p.Ser7= Likely benign ★★ same residue
DSC2 p.Ser7Cys Uncertain significance ★ ⚠ same residue
DSC2 p.Ser7Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
DSC2 p.Ser7Pro 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

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-arg7pro (accessed [today's date]).

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