Is DES p.Arg454Trp (c.1360C>T) pathogenic?

DES p.Arg454Trp (c.1360C>T) is classified Pathogenic/Likely pathogenic in DES (ClinVar, Multiple submitters, 15 submitters; last evaluated 2025-10-15). AlphaMissense: likely pathogenic (0.6938); Very rare (popmax 0.00224%, eas); Associated with Cardiovascular phenotype.

What condition is associated with DES p.Arg454Trp (c.1360C>T)?

DES p.Arg454Trp (c.1360C>T) is associated with Cardiovascular phenotype, dilated cardiomyopathy, neurogenic scapuloperoneal syndrome, Kaeser type (ClinVar).

How common is DES p.Arg454Trp (c.1360C>T) in the general population?

DES p.Arg454Trp (c.1360C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about DES p.Arg454Trp (c.1360C>T)?

AlphaMissense predicts likely pathogenic (score 0.6938) — an in-silico prediction, not a clinical call.

DES p.Arg454Trp

c.1360C>T · rs267607490 · VCV66402

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

AlphaMissense

likely pathogenic

0.6938 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.6938	likely pathogenic ✓ concordant with ClinVar
REVEL	0.919	moderately pathogenic-leaning
SaProt	LLR -14.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	33.0	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 0.00224% East Asian · 1/44,598 alleles

Overall 6.89e-05% 1/1,452,416 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.Arg454Trp
Coding: c.1360C>T
MANE Select: NM_001927
dbSNP: rs267607490
Type: single nucleotide variant
Location: chr2:219425734 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 454: the 'tail' region; a UniProt-annotated variant site (in mfm1; reveals a severe disturbance of filament-formation competence and filament-filament interactions; increased interaction with cryab)

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy neurogenic scapuloperoneal syndrome, Kaeser type myofibrillar myopathy 1 dilated cardiomyopathy 1I neuromuscular disease

Similar variants

DES p.Arg454Gln Uncertain significance ★★ ⚠ same residue
DES p.Arg454= Likely benign ★★ 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-arg454trp (accessed [today's date]).

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