Is DES p.Thr76fs (c.226del) pathogenic?

DES p.Thr76fs (c.226del) is classified Pathogenic/Likely pathogenic in DES (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-12-10). Very rare (popmax 0.00269%, afr); Associated with neurogenic scapuloperoneal syndrome, Kaeser type.

What condition is associated with DES p.Thr76fs (c.226del)?

DES p.Thr76fs (c.226del) is associated with neurogenic scapuloperoneal syndrome, Kaeser type, myofibrillar myopathy 1, dilated cardiomyopathy 1I (ClinVar).

How common is DES p.Thr76fs (c.226del) in the general population?

DES p.Thr76fs (c.226del) is very rare (popmax 0.00269%, afr) (gnomAD).

DES p.Thr76fs

Q: How is Neurogenic scapuloperoneal syndrome, Kaeser type inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.226del · rs1399282762 · VCV643624

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00269%, afr)

Conditions

neurogenic scapuloperoneal syndrome, Kaeser type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.64	GERP -3, phastCons 0.3
Overall
CADD	12.22	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	G-rich low complexity · ambiguous alignment · confidence, not pathogenicity

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00269% African / African-American · 2/74,318 alleles

Filtering AF 0.00113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000916%

Overall 0.0014% 22/1,573,162 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00269%	37,159
European (non-Finnish)	0.00172%	57,977

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: DES
Protein: p.Thr76fs
Coding: c.226del
MANE Select: NM_001927
dbSNP: rs1399282762
Type: Deletion
Location: chr2:219418688 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 76: a modified residue (phosphothreonine; by rock1); the 'head' region

Full DES gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurogenic scapuloperoneal syndrome, Kaeser type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: myofibrillar myopathy 1 dilated cardiomyopathy 1I

For Neurogenic scapuloperoneal syndrome, Kaeser type (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

DES p.Thr76= Likely benign ★★ same residue
DES p.Ala134fs Pathogenic/Likely pathogenic ★★ same condition
DES p.Pro419fs Pathogenic ★★ same condition
DES p.Tyr405fs Pathogenic ★★ same condition
DES p.Glu179_Leu184del Uncertain significance ★★ same condition
DES p.Glu387del Uncertain significance ★★ same condition
DES p.Lys449_Ile451del Uncertain significance ★★ same condition
DES c.897+4_897+5del Benign/Likely benign ★★ 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/des-p-thr76fs (accessed [today's date]).

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