Is DES p.Ile451= (c.1353C>T) pathogenic?

DES p.Ile451= (c.1353C>T) is classified Conflicting classifications of pathogenicity in DES (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-02-04). Rare (popmax 0.368%, eas); Associated with Cardiovascular phenotype.

What condition is associated with DES p.Ile451= (c.1353C>T)?

DES p.Ile451= (c.1353C>T) is associated with Cardiovascular phenotype, cardiomyopathy, myofibrillar myopathy 1 (ClinVar).

How common is DES p.Ile451= (c.1353C>T) in the general population?

DES p.Ile451= (c.1353C>T) is rare (popmax 0.368%, eas) (gnomAD).

DES p.Ile451=

c.1353C>T · rs121913002 · VCV226559

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

rare (popmax 0.368%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -15	GERP -3.4
Overall
CADD	2.518	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.368% East Asian · 164/44,560 alleles

Filtering AF 0.322% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.304%

Overall 0.0139% 223/1,602,978 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.368%	272
Remaining individualsnot grpmax-eligible	0.0498%	2,006
South Asian	0.0203%	4,923
African / African-American	0.00401%	24,926
Admixed American	0.00344%	29,082
Finnishnot grpmax-eligible	0.00157%	63,504
European (non-Finnish)	0.00034%	293,755

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.Ile451=
Coding: c.1353C>T
MANE Select: NM_001927
dbSNP: rs121913002
Type: single nucleotide variant
Location: chr2:219425727 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 451: the 'tail' region; the 'interaction with cryab' region; a UniProt-annotated variant site (in cmd1i and mfm1; reveals a severe disturbance of filament-formation competence and filament-filament interactions; reduced 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: cardiomyopathy myofibrillar myopathy 1

Similar variants

DES p.Ile451Met Conflicting classifications of pathogenicity ★ ⚠ 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
DES p.Ala285Val 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-ile451 (accessed [today's date]).

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