Is DST p.Arg1250Ter (c.3748C>T) pathogenic?

DST p.Arg1250Ter (c.3748C>T) is classified Conflicting classifications of pathogenicity in DST (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-03-19). Very rare (popmax 0.00329%, sas); Associated with hereditary sensory and autonomic neuropathy type 6.

What condition is associated with DST p.Arg1250Ter (c.3748C>T)?

DST p.Arg1250Ter (c.3748C>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.Arg1250Ter (c.3748C>T) in the general population?

DST p.Arg1250Ter (c.3748C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

DST p.Arg1250Ter

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.3748C>T · rs779271284 · VCV1324300

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00329%, 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.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 0.11, phastCons 1
Overall
CADD	16.42	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,070 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00124% 20/1,613,740 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,701
South Asiangrpmax	0.00329%	30,357
East Asian	0.00223%	44,866
Admixed American	0.00167%	59,980
African / African-American	0.00134%	74,808
European (non-Finnish)	0.000508%	196,666

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.Arg1250Ter
Coding: c.3748C>T
MANE Select: NM_001374736 · reported on NM_001723
dbSNP: rs779271284
Type: single nucleotide variant
Location: chr6:56620286 (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.Arg1250Gln 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
DST p.Gln1124Ter 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-arg1250ter (accessed [today's date]).

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