Is DST p.Ser5499Cys (c.16495A>T) pathogenic?

DST p.Ser5499Cys (c.16495A>T) is classified Conflicting classifications of pathogenicity in DST (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-11). Rare (popmax 0.154%, nfe); Associated with hereditary sensory and autonomic neuropathy type 6.

What condition is associated with DST p.Ser5499Cys (c.16495A>T)?

DST p.Ser5499Cys (c.16495A>T) 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.Ser5499Cys (c.16495A>T) in the general population?

DST p.Ser5499Cys (c.16495A>T) is rare (popmax 0.154%, nfe) (gnomAD).

DST p.Ser5499Cys

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.16495A>T · rs180765536 · VCV795733

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.154%, 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.
REVEL	0.05	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 1.9, phastCons 0.86
Regional constraint	o/e 1.02	unconstrained · MANE · 35 kb · p 0.66 · regional, not allelic
Overall
CADD	15.14	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.154% European (non-Finnish) · 1,814/1,179,892 alleles

Filtering AF 0.148% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.145%

Overall 0.129% 2,076/1,614,022 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.154%	650
South Asian	0.143%	701
Remaining individualsnot grpmax-eligible	0.0736%	1,358
Finnishnot grpmax-eligible	0.0687%	1,455
Admixed American	0.04%	2,501
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,229
Middle Eastern	0.0165%	6,062
African / African-American	0.012%	8,339
East Asian	0.00223%	44,878

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.Ser5499Cys
Coding: c.16495A>T
MANE Select: NM_001374736
dbSNP: rs180765536
Type: single nucleotide variant
Location: chr6:56552297 (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
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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-ser5499cys (accessed [today's date]).

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