Is DST p.Ala7221Val (c.21662C>T) pathogenic?

DST p.Ala7221Val (c.21662C>T) is classified Uncertain significance in DST (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-03-31). Very rare (popmax 0.00398%, nfe); Associated with Inborn genetic diseases.

How common is DST p.Ala7221Val (c.21662C>T) in the general population?

DST p.Ala7221Val (c.21662C>T) is very rare (popmax 0.00398%, nfe) (gnomAD).

DST p.Ala7221Val

Q: What condition is associated with DST p.Ala7221Val (c.21662C>T)?

DST p.Ala7221Val (c.21662C>T) 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.21662C>T · rs376556021 · VCV970596

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00398%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.338	indeterminate
Splicing
SpliceAI	Δ0.60	donor gain · deltas
Pangolin	Δ0.40	gain · loss 0.11 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 46 kb · p 3.7e-11 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00398% European (non-Finnish) · 47/1,179,804 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.00316% 51/1,613,618 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00398%	25,102
Remaining individualsnot grpmax-eligible	0.0032%	31,226
East Asian	0.00223%	44,880
South Asian	0.0011%	91,046

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.Ala7221Val
Coding: c.21662C>T
MANE Select: NM_001374736
dbSNP: rs376556021
Type: single nucleotide variant
Location: chr6:56477358 (GRCh38)
Gene constraint: LOEUF 0.297 · pLI 1.00 (gnomAD)
Residue 7221: the ef-hand 1 domain; a binding site

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.Ala7221= Likely benign ★ 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-ala7221val (accessed [today's date]).

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