Is DSC3 p.Glu820Ter (c.2458G>T) pathogenic?

DSC3 p.Glu820Ter (c.2458G>T) is classified Likely pathogenic in DSC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-10). Very rare (popmax 0.0011%, sas); Associated with hereditary hypotrichosis with recurrent skin vesicles.

What condition is associated with DSC3 p.Glu820Ter (c.2458G>T)?

DSC3 p.Glu820Ter (c.2458G>T) is associated with hereditary hypotrichosis with recurrent skin vesicles (ClinVar).

How common is DSC3 p.Glu820Ter (c.2458G>T) in the general population?

DSC3 p.Glu820Ter (c.2458G>T) is very rare (popmax 0.0011%, sas) (gnomAD).

DSC3 p.Glu820Ter

Q: How is Hereditary hypotrichosis with recurrent skin vesicles inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.2458G>T · VCV4845663

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

hereditary hypotrichosis with recurrent skin vesicles

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.20	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Overall
CADD	43.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,042 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000752% 11/1,461,824 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,498
South Asiangrpmax	0.0011%	91,042
European (non-Finnish)	0.000763%	131,107

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu820Ter
Coding: c.2458G>T
MANE Select: NM_024422 · reported on NM_001941
Type: single nucleotide variant
Location: chr18:30996826 (GRCh38)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 820: a UniProt-annotated variant site (in arvd11; likely pathogenic; mislocalization of dsc2 to the cytoplasm within intercalated disks of the heart)

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

Disease context

hereditary hypotrichosis with recurrent skin vesicles — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary hypotrichosis with recurrent skin vesicles (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

DSC2 p.Arg820= Uncertain significance ★★ same residue
DSC2 p.Arg820Gly Uncertain significance ★ ⚠ same residue
DSC3 c.2236-2A>G Likely pathogenic ★★ same condition
DSC3 c.2493+1G>A Likely pathogenic ★ same condition
DSC3 p.Arg375Ter Likely pathogenic ★ same condition
DSC3 p.Leu710Ter Pathogenic same condition
DSC3 p.Leu727Ter Pathogenic same condition
DSC3 p.Glu427fs Likely pathogenic ★ 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/dsc3-p-glu820ter (accessed [today's date]).

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