Is DST p.Arg1239Cys (c.3715C>T) pathogenic?

DST p.Arg1239Cys (c.3715C>T) is classified Uncertain significance in DST (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-07). Ultra-rare (popmax 0.0493%, mid); Associated with epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency.

How common is DST p.Arg1239Cys (c.3715C>T) in the general population?

DST p.Arg1239Cys (c.3715C>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

DST p.Arg1239Cys

Q: What condition is associated with DST p.Arg1239Cys (c.3715C>T)?

DST p.Arg1239Cys (c.3715C>T) is associated with epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency, hereditary sensory and autonomic neuropathy type 6 (ClinVar).

Q: How is Epidermolysis bullosa simplex due to BP230 deficiency inherited?

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

c.3715C>T · rs371231287 · VCV357585

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Conditions

epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.063	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 2.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 36 kb · p 0.7 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0263%

Overall 0.00297% 48/1,613,966 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
East Asian	0.0468%	2,137
Admixed American	0.00333%	29,995
European (non-Finnish)	0.00169%	59,002
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-American	0.00134%	74,896

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: DST
Protein: p.Arg1239Cys
Coding: c.3715C>T
MANE Select: NM_001374736 · reported on NM_001723
dbSNP: rs371231287
Type: single nucleotide variant
Location: chr6:56620319 (GRCh38)
Gene constraint: LOEUF 0.297 · pLI 1.00 (gnomAD)

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

Disease context

epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary sensory and autonomic neuropathy type 6

For Epidermolysis bullosa simplex due to BP230 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult

Similar variants

DST p.Arg1239His Uncertain significance ★ same residue
DST p.Val1239= Benign ★ same residue
DST c.22959+1G>A Likely pathogenic ★★ same condition
DST p.Arg1512Ter Pathogenic/Likely pathogenic ★★ same condition
DST p.Arg1696Ter Pathogenic/Likely pathogenic ★★ same condition
DST p.Arg22Ter Likely pathogenic ★★ same condition
DST p.Arg7329Ter Pathogenic ★★ same condition
DST p.Cys1828Ter Pathogenic/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/dst-p-arg1239cys (accessed [today's date]).

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