Is DST p.Ala1125Val (c.3374C>T) pathogenic?

DST p.Ala1125Val (c.3374C>T) is classified Uncertain significance in DST (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-28). Ultra-rare (popmax 0.0318%, sas); Associated with hereditary sensory and autonomic neuropathy type 6.

What condition is associated with DST p.Ala1125Val (c.3374C>T)?

DST p.Ala1125Val (c.3374C>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.Ala1125Val (c.3374C>T) in the general population?

DST p.Ala1125Val (c.3374C>T) is ultra-rare (popmax 0.0318%, sas) (gnomAD).

DST p.Ala1125Val

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.3374C>T · rs766653025 · VCV1050899

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0318%, sas)

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	0.226	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 320 kb · p 2.5e-12 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0318% South Asian · 29/91,072 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0196%

Overall 0.00254% 41/1,613,946 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0318%	3,140
East Asian	0.00668%	14,964
Admixed American	0.00667%	14,997
African / African-American	0.00534%	18,720
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Ala1125Val
Coding: c.3374C>T
MANE Select: NM_001374736
dbSNP: rs766653025
Type: single nucleotide variant
Location: chr6:56634582 (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 p.Ala1125= Likely benign ★★ same residue
DST p.Arg1125Cys Uncertain significance ★ same residue
DST p.Arg1125His Uncertain significance ★ same residue
DST p.Arg1125Leu Uncertain significance ★ same residue
DST p.Arg1125Pro Uncertain significance ★ same residue
DST p.Arg1125= Likely benign ★ same residue
DST c.22959+1G>A Likely pathogenic ★★ same condition
DST p.Arg1512Ter 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-ala1125val (accessed [today's date]).

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