Is DST p.Leu6999= (c.20997G>A) pathogenic?

DST p.Leu6999= (c.20997G>A) is classified Benign/Likely benign in DST (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-06-01). Low-frequency (popmax 1.41%, nfe); Associated with hereditary sensory and autonomic neuropathy type 6.

What condition is associated with DST p.Leu6999= (c.20997G>A)?

DST p.Leu6999= (c.20997G>A) is associated with hereditary sensory and autonomic neuropathy type 6, epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency (ClinVar).

How common is DST p.Leu6999= (c.20997G>A) in the general population?

DST p.Leu6999= (c.20997G>A) is low-frequency (popmax 1.41%, nfe) (gnomAD).

DST p.Leu6999=

Q: How is Hereditary sensory and autonomic neuropathy type 6 inherited?

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

c.20997G>A · rs187652380 · VCV522337

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.41%, nfe)

Conditions

hereditary sensory and autonomic neuropathy type 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.26	GERP -1.7, phastCons 0.22
Overall
CADD	4.505	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.41% European (non-Finnish) · 16,688/1,179,826 alleles

Filtering AF 1.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.39%

Overall 1.14% 18,352/1,613,914 alleles · low-frequency

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.41%	71
Remaining individualsnot grpmax-eligible	0.97%	103
Admixed American	0.703%	142
Finnishnot grpmax-eligible	0.695%	144
African / African-American	0.25%	399
Middle Eastern	0.0165%	6,062
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
South Asian	0.0011%	91,074

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.Leu6999=
Coding: c.20997G>A
MANE Select: NM_001374736
dbSNP: rs187652380
Type: single nucleotide variant
Location: chr6:56487154 (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

hereditary sensory and autonomic neuropathy type 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Hereditary sensory and autonomic neuropathy type 6 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

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
DST p.Gln1366Ter 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-leu6999 (accessed [today's date]).

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