Is DES p.Ile451Met (c.1353C>G) pathogenic?

DES p.Ile451Met (c.1353C>G) is classified Conflicting classifications of pathogenicity in DES (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-01-06). AlphaMissense: likely pathogenic (0.5878); Very rare (popmax 0.00536%, afr); Associated with Cardiovascular phenotype.

What condition is associated with DES p.Ile451Met (c.1353C>G)?

DES p.Ile451Met (c.1353C>G) is associated with Cardiovascular phenotype, myofibrillar myopathy 1, dilated cardiomyopathy 1I (ClinVar).

How common is DES p.Ile451Met (c.1353C>G) in the general population?

DES p.Ile451Met (c.1353C>G) is very rare (popmax 0.00536%, afr) (gnomAD).

What do computational predictors say about DES p.Ile451Met (c.1353C>G)?

AlphaMissense predicts likely pathogenic (score 0.5878) — an in-silico prediction, not a clinical call.

DES p.Ile451Met

c.1353C>G · rs121913002 · VCV16824

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

likely pathogenic

0.5878 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00536%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5878	likely pathogenic
REVEL	0.692	pathogenic-leaning
SaProt	LLR -9.90	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -15	GERP -3.4
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	9.078	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 0.00536% African / African-American · 4/74,656 alleles

Filtering AF 0.00395% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00362%

Overall 0.00424% 68/1,602,862 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00536%	18,664
European (non-Finnish)	0.00502%	19,916
Remaining individualsnot grpmax-eligible	0.00483%	20,725
Admixed American	0.00344%	29,072

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.Ile451Met
Coding: c.1353C>G
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: myofibrillar myopathy 1 dilated cardiomyopathy 1I

Similar variants

DES p.Ile451= 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-ile451met (accessed [today's date]).

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