Is DES p.Ala360Ser (c.1078G>T) pathogenic?

DES p.Ala360Ser (c.1078G>T) is classified Uncertain significance in DES (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-16). AlphaMissense: likely benign (0.136); Very rare (popmax 8.47e-05%, nfe); Associated with neurogenic scapuloperoneal syndrome, Kaeser type.

What condition is associated with DES p.Ala360Ser (c.1078G>T)?

DES p.Ala360Ser (c.1078G>T) is associated with neurogenic scapuloperoneal syndrome, Kaeser type, myofibrillar myopathy 1, dilated cardiomyopathy 1I (ClinVar).

How common is DES p.Ala360Ser (c.1078G>T) in the general population?

DES p.Ala360Ser (c.1078G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about DES p.Ala360Ser (c.1078G>T)?

AlphaMissense predicts likely benign (score 0.136) — an in-silico prediction, not a clinical call.

DES p.Ala360Ser

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

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

c.1078G>T · rs121913000 · VCV1517261

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.136 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurogenic scapuloperoneal syndrome, Kaeser type

Computational evidence

Protein change
AlphaMissense	0.136	likely benign
REVEL	0.722	pathogenic-leaning
SaProt	LLR -6.24	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.84e-05% 1/1,461,884 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.Ala360Ser
Coding: c.1078G>T
MANE Select: NM_001927
dbSNP: rs121913000
Type: single nucleotide variant
Location: chr2:219421394 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 360: the 'coil 2b' region; the if rod domain; a UniProt-annotated variant site (in mfm1); a UniProt-annotated variant site (in mfm1; heterozygous with i-393 gives a severe childhood-onset; unable to form a functional filamentous network in the presence of i-393; abolishes binding to mtm1); the 'interaction with neb' 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.Ala360Val Uncertain significance ★★ ⚠ same residue
DES p.Ala360Pro Pathogenic same residue
DES c.1289-2A>G Pathogenic/Likely pathogenic ★★ same condition
DES c.579-2A>C Likely pathogenic ★★ same condition
DES c.735+1G>A Pathogenic/Likely pathogenic ★★ same condition
DES c.735+1G>C Pathogenic/Likely pathogenic ★★ same condition
DES c.735+3A>G Pathogenic ★★ same condition
DES p.Ala120Pro 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/des-p-ala360ser (accessed [today's date]).

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