Is DST p.Ser2649Phe (c.7946C>T) pathogenic?

DST p.Ser2649Phe (c.7946C>T) is classified Uncertain significance in DST (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-18). Ultra-rare (popmax 0.066%, mid); Associated with epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency.

How common is DST p.Ser2649Phe (c.7946C>T) in the general population?

DST p.Ser2649Phe (c.7946C>T) is ultra-rare (popmax 0.066%, mid) (gnomAD).

DST p.Ser2649Phe

Q: What condition is associated with DST p.Ser2649Phe (c.7946C>T)?

DST p.Ser2649Phe (c.7946C>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.7946C>T · rs773910675 · VCV658213

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, 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	0.278	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 2.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 36 kb · p 0.7 · regional, not allelic
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.066% Middle Eastern · 4/6,060 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.00787% 127/1,613,976 alleles · ultra-rare exomes 120/1,461,708 · genomes 7/152,268 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.066%	1,515
South Asian	0.0307%	3,253
Remaining individualsnot grpmax-eligible	0.0256%	3,906
European (non-Finnish)	0.0061%	16,388
Admixed American	0.005%	19,998
Finnishnot grpmax-eligible	0.00312%	32,004
African / African-American	0.00267%	37,511

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.Ser2649Phe
Coding: c.7946C>T
MANE Select: NM_001374736 · reported on NM_001723
dbSNP: rs773910675
Type: single nucleotide variant
Location: chr6:56615521 (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.Ser2649= Likely 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
DST p.Gln1124Ter 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-ser2649phe (accessed [today's date]).

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