Is DSC3 p.Arg199Leu (c.596G>T) pathogenic?

DSC3 p.Arg199Leu (c.596G>T) is classified Uncertain significance in DSC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely benign (0.2106); Very rare (popmax 0.00401%, afr).

How common is DSC3 p.Arg199Leu (c.596G>T) in the general population?

DSC3 p.Arg199Leu (c.596G>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about DSC3 p.Arg199Leu (c.596G>T)?

AlphaMissense predicts likely benign (score 0.2106) — an in-silico prediction, not a clinical call.

DSC3 p.Arg199Leu

c.596G>T · VCV4244929

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2106 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2106	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -10.23	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 -4.9	GERP -4
Overall
CADD	9.188	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 0.00401% African / African-American · 3/74,810 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00031% 5/1,612,956 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,937
Admixed American	0.00167%	59,910
Remaining individualsnot grpmax-eligible	0.0016%	62,450

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.Arg199Leu
Coding: c.596G>T
MANE Select: NM_024422 · reported on NM_001941
Type: single nucleotide variant
Location: chr18:31025794 (GRCh38)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 199: the cadherin 1 domain

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

Similar variants

DSC3 p.Arg199Gln Likely benign ★ same residue
DSC3 p.Arg199Trp Benign ⚠ 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

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-arg199leu (accessed [today's date]).

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