Is DST p.Leu4454Ser (c.13361T>C) pathogenic?

DST p.Leu4454Ser (c.13361T>C) is classified Conflicting classifications of pathogenicity in DST (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-01). Ultra-rare (popmax 0.0825%, mid); Associated with Inborn genetic diseases.

How common is DST p.Leu4454Ser (c.13361T>C) in the general population?

DST p.Leu4454Ser (c.13361T>C) is ultra-rare (popmax 0.0825%, mid) (gnomAD).

DST p.Leu4454Ser

Q: What condition is associated with DST p.Leu4454Ser (c.13361T>C)?

DST p.Leu4454Ser (c.13361T>C) is associated with Inborn genetic diseases, hereditary sensory and autonomic neuropathy type 6, epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency (ClinVar).

c.13361T>C · rs201758531 · VCV489326

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 0.0825%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.442	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 46 kb · p 5.7e-05 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0825% Middle Eastern · 5/6,062 alleles

Filtering AF 0.037% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.0173% 279/1,613,168 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.321%	311
Middle Easterngrpmax	0.0825%	1,212
South Asian	0.0484%	2,067
Remaining individualsnot grpmax-eligible	0.0449%	2,230
European (non-Finnish)	0.00882%	11,342
Admixed American	0.00334%	29,911
Finnishnot grpmax-eligible	0.00156%	63,930

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.Leu4454Ser
Coding: c.13361T>C
MANE Select: NM_001374736
dbSNP: rs201758531
Type: single nucleotide variant
Location: chr6:56572940 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary sensory and autonomic neuropathy type 6 epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency

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-leu4454ser (accessed [today's date]).

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