Is DES p.Lys378fs (c.1132_1153del) pathogenic?

DES p.Lys378fs (c.11321153del) is classified Pathogenic in DES (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-10). Very rare (popmax 8.47e-05%, nfe); Associated with myofibrillar myopathy 1.

What condition is associated with DES p.Lys378fs (c.1132_1153del)?

DES p.Lys378fs (c.1132_1153del) is associated with myofibrillar myopathy 1 (ClinVar).

How common is DES p.Lys378fs (c.1132_1153del) in the general population?

DES p.Lys378fs (c.1132_1153del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Desminopathy inherited?

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

DES p.Lys378fs

c.1132_1153del · rs1575014943 · VCV641138

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

myofibrillar myopathy 1

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 6 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.3	GERP -0.54, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,006 alleles

Overall 6.84e-05% 1/1,461,856 alleles · very rare

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.Lys378fs
Coding: c.1132_1153del
MANE Select: NM_001927
dbSNP: rs1575014943
Type: Deletion
Location: chr2:219421446 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 378: the 'coil 2b' region; the if rod domain; the 'interaction with neb' region

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

Disease context

myofibrillar myopathy 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Desminopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy

Similar variants

DES p.Lys378Arg Uncertain significance ★ ⚠ same residue
DES p.Lys378= Likely benign ★ same residue
DES p.Ala134fs Pathogenic/Likely pathogenic ★★ same condition
DES p.Pro419fs Pathogenic ★★ same condition
DES p.Thr76fs Pathogenic/Likely pathogenic ★★ same condition
DES p.Tyr405fs Pathogenic ★★ same condition
DES p.Glu179_Leu184del Uncertain significance ★★ same condition
DES p.Glu387del Uncertain significance ★★ 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-lys378fs (accessed [today's date]).

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