Is DSC1 p.Met659Arg (c.1976T>G) pathogenic?

DSC1 p.Met659Arg (c.1976T>G) is classified Benign in DSC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-27). AlphaMissense: likely benign (0.1074); Low-frequency (popmax 3.86%, afr).

How common is DSC1 p.Met659Arg (c.1976T>G) in the general population?

DSC1 p.Met659Arg (c.1976T>G) is low-frequency (popmax 3.86%, afr) (gnomAD).

What do computational predictors say about DSC1 p.Met659Arg (c.1976T>G)?

AlphaMissense predicts likely benign (score 0.1074) — an in-silico prediction, not a clinical call.

DSC1 p.Met659Arg

c.1976T>G · rs28620831 · VCV714749

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1074 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.86%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1074	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -7.04	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 1.7	GERP -2.2
Regional constraint	o/e 1.04	unconstrained · MANE · 32 kb · p 0.23 · regional, not allelic
Overall
CADD	8.668	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 3.86% African / African-American · 2,891/74,986 alleles

Filtering AF 3.74% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.69%

Overall 0.204% 3,297/1,613,072 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.86%	26
Remaining individualsnot grpmax-eligible	0.336%	297
Admixed American	0.268%	373
Middle Eastern	0.149%	673
South Asian	0.00439%	22,766
European (non-Finnish)	0.00186%	53,620

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: DSC1
Protein: p.Met659Arg
Coding: c.1976T>G
MANE Select: NM_024421
dbSNP: rs28620831
Type: single nucleotide variant
Location: chr18:31134031 (GRCh38)
Gene constraint: LOEUF 0.951 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.16 · 1 PDB
Residue 659: the cadherin 5 domain; a β-strand

Full DSC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DSC1 p.Ile200Thr Benign ★★ ⚠ same type
DSC1 p.Thr710= Benign ★★ same type
DSC1 p.Ala128Pro Uncertain significance ★ ⚠ same type
DSC1 p.Ala209Val Uncertain significance ★ ⚠ same type
DSC1 p.Ala221Glu Uncertain significance ★ ⚠ same type
DSC1 p.Ala239Thr Uncertain significance ★ ⚠ same type
DSC1 p.Ala574Thr Uncertain significance ★ ⚠ same type
DSC1 p.Ala693Val Uncertain significance ★ ⚠ 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/dsc1-p-met659arg (accessed [today's date]).

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