Is DSC3 p.Arg375Ter (c.1123C>T) pathogenic?

DSC3 p.Arg375Ter (c.1123C>T) is classified Likely pathogenic in DSC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-05). Very rare (popmax 0.00448%, eas); Associated with hereditary hypotrichosis with recurrent skin vesicles.

What condition is associated with DSC3 p.Arg375Ter (c.1123C>T)?

DSC3 p.Arg375Ter (c.1123C>T) is associated with hereditary hypotrichosis with recurrent skin vesicles (ClinVar).

How common is DSC3 p.Arg375Ter (c.1123C>T) in the general population?

DSC3 p.Arg375Ter (c.1123C>T) is very rare (popmax 0.00448%, eas) (gnomAD).

DSC3 p.Arg375Ter

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.1123C>T · rs771238740 · VCV2441782

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 0.00448%, eas)

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
Constraint at this position
Conservation	phyloP 3	GERP 1.1, phastCons 1
Overall
CADD	36.0	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 0.00448% East Asian · 2/44,670 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000496%

Overall 0.000869% 14/1,611,446 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00448%	22,335
African / African-American	0.00401%	24,915
Remaining individualsnot grpmax-eligible	0.0016%	62,354
Finnishnot grpmax-eligible	0.00157%	63,630
European (non-Finnish)	0.000594%	168,406

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.Arg375Ter
Coding: c.1123C>T
MANE Select: NM_024422 · reported on NM_001941
dbSNP: rs771238740
Type: single nucleotide variant
Location: chr18:31018211 (GRCh38)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 375: a β-strand; the cadherin 3 domain

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.Arg375Gln Uncertain significance ★★ ⚠ same residue
DSC2 p.Arg375Gly Uncertain significance ★★ ⚠ same residue
DSC2 p.Arg375= Likely benign ★ same residue
DSC3 c.2236-2A>G Likely pathogenic ★★ same condition
DSC3 c.2493+1G>A Likely pathogenic ★ same condition
DSC3 p.Glu820Ter Likely pathogenic ★ same condition
DSC2 p.Arg375fs Uncertain significance ★ same residue
DSC3 p.Leu710Ter 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-arg375ter (accessed [today's date]).

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