Is DSC1 p.His842Arg (c.2525A>G) pathogenic?

DSC1 p.His842Arg (c.2525A>G) is classified Uncertain significance in DSC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: likely benign (0.0947); Very rare (popmax 0.00266%, afr).

How common is DSC1 p.His842Arg (c.2525A>G) in the general population?

DSC1 p.His842Arg (c.2525A>G) is very rare (popmax 0.00266%, afr) (gnomAD).

What do computational predictors say about DSC1 p.His842Arg (c.2525A>G)?

AlphaMissense predicts likely benign (score 0.0947) — an in-silico prediction, not a clinical call.

DSC1 p.His842Arg

c.2525A>G · VCV4662213

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0947 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0947	likely benign
REVEL	0.347	indeterminate
SaProt	LLR -6.20	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.78	GERP -0.58, phastCons 0.93
Regional constraint	o/e 1.04	unconstrained · MANE · 32 kb · p 0.23 · regional, not allelic
Overall
CADD	16.13	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 0.00266% African / African-American · 2/75,052 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000205% 3/1,461,864 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00266%	37,526
European (non-Finnish)	8.47e-05%	1,180,022

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.His842Arg
Coding: c.2525A>G
MANE Select: NM_024421
Type: single nucleotide variant
Location: chr18:31130674 (GRCh38)
Gene constraint: LOEUF 0.951 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.16 · 1 PDB

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

Similar variants

DSC1 p.Ile200Thr Benign ★★ ⚠ same type
DSC1 p.Met659Arg 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

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-his842arg (accessed [today's date]).

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