Is DST p.Leu4531Val (c.13591C>G) pathogenic?

DST p.Leu4531Val (c.13591C>G) is classified Uncertain significance in DST (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-30). Very rare (popmax 0.0027%, afr); Associated with Inborn genetic diseases.

How common is DST p.Leu4531Val (c.13591C>G) in the general population?

DST p.Leu4531Val (c.13591C>G) is very rare (popmax 0.0027%, afr) (gnomAD).

DST p.Leu4531Val

Q: What condition is associated with DST p.Leu4531Val (c.13591C>G)?

DST p.Leu4531Val (c.13591C>G) 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.13591C>G · rs996209535 · VCV1008233

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0027%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.06	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 46 kb · p 5.7e-05 · regional, not allelic
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0027% African / African-American · 2/74,168 alleles

Filtering AF 0.000448% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000318%

Overall 0.00089% 14/1,573,882 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0027%	37,084
East Asian	0.00228%	43,818
Remaining individualsnot grpmax-eligible	0.00165%	60,756
European (non-Finnish)	0.000863%	115,922

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.Leu4531Val
Coding: c.13591C>G
MANE Select: NM_001374736
dbSNP: rs996209535
Type: single nucleotide variant
Location: chr6:56572230 (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 p.Leu4531His Uncertain significance ★ same residue
DST p.Leu4531Pro 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

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-leu4531val (accessed [today's date]).

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