Is DES p.Ala134fs (c.400_410del) pathogenic?

DES p.Ala134fs (c.400410del) is classified Pathogenic/Likely pathogenic in DES (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-08). Very rare (popmax 0.00463%, sas); Associated with myofibrillar myopathy 1.

What condition is associated with DES p.Ala134fs (c.400_410del)?

DES p.Ala134fs (c.400_410del) is associated with myofibrillar myopathy 1 (ClinVar).

How common is DES p.Ala134fs (c.400_410del) in the general population?

DES p.Ala134fs (c.400_410del) is very rare (popmax 0.00463%, sas) (gnomAD).

How is Desminopathy inherited?

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

DES p.Ala134fs

c.400_410del · rs1954374671 · VCV2637262

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00463%, sas)

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 1 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Overall
CADD	35.0	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 0.00463% South Asian · 4/86,412 alleles

Filtering AF 0.00158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000928%

Overall 0.000253% 4/1,578,500 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.Ala134fs
Coding: c.400_410del
MANE Select: NM_001927
dbSNP: rs1954374671
Type: Deletion
Location: chr2:219418861 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 134: the if rod domain; the 'coil 1a' 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.Ala134Glu Uncertain significance ★ same residue
DES p.Ala134= Likely benign ★ same residue
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
DES p.Lys449_Ile451del 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-ala134fs (accessed [today's date]).

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