Is DST p.Met709Val (c.2125A>G) pathogenic?

DST p.Met709Val (c.2125A>G) is classified Conflicting classifications of pathogenicity in DST (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-27). Ultra-rare (popmax 0.0783%, amr); Associated with epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency.

How common is DST p.Met709Val (c.2125A>G) in the general population?

DST p.Met709Val (c.2125A>G) is ultra-rare (popmax 0.0783%, amr) (gnomAD).

DST p.Met709Val

Q: What condition is associated with DST p.Met709Val (c.2125A>G)?

DST p.Met709Val (c.2125A>G) 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.2125A>G · rs142650835 · VCV357618

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0783%, amr)

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	0.231	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP 0.56, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 320 kb · p 2.5e-12 · regional, not allelic
Overall
CADD	18.24	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0783% Admixed American · 47/60,028 alleles

Filtering AF 0.0685% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0669%

Overall 0.0668% 1,078/1,613,620 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.382%	262
Admixed Americangrpmax	0.0783%	1,277
European (non-Finnish)	0.0726%	1,378
Remaining individualsnot grpmax-eligible	0.0656%	1,524
South Asian	0.0165%	6,072
African / African-American	0.00666%	15,010
Finnishnot grpmax-eligible	0.00156%	64,044

Ashkenazi Jewish 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: DST
Protein: p.Met709Val
Coding: c.2125A>G
MANE Select: NM_001374736
dbSNP: rs142650835
Type: single nucleotide variant
Location: chr6:56640508 (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.Met709Leu Uncertain significance ★ 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-met709val (accessed [today's date]).

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