Is DES p.Ile223= (c.669T>C) pathogenic?

DES p.Ile223= (c.669T>C) is classified Benign/Likely benign in DES (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-02-03). Common (popmax 9.05%, afr) — too common for a highly-penetrant pathogenic allele; Associated with myofibrillar myopathy 1.

What condition is associated with DES p.Ile223= (c.669T>C)?

DES p.Ile223= (c.669T>C) is associated with myofibrillar myopathy 1, cardiomyopathy, neurogenic scapuloperoneal syndrome, Kaeser type (ClinVar).

How is Desminopathy inherited?

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

DES p.Ile223=

Q: How common is DES p.Ile223= (c.669T>C) in the general population?

DES p.Ile223= (c.669T>C) is common (popmax 9.05%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.669T>C · rs75882680 · VCV36001

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

gnomAD v4.1

Common

common (popmax 9.05%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

myofibrillar myopathy 1

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 0.35	GERP -3.3, phastCons 1
Overall
CADD	10.75	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.05% African / African-American · 6,793/75,028 alleles

Filtering AF 8.87% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.8%

Overall 0.541% 8,730/1,614,180 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.05%	11
Admixed American	0.846%	118
Remaining individualsnot grpmax-eligible	0.738%	136
Middle Eastern	0.726%	138
Ashkenazi Jewishnot grpmax-eligible	0.155%	644
European (non-Finnish)	0.0731%	1,367
South Asian	0.0154%	6,506
Finnishnot grpmax-eligible	0.00156%	64,042

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.Ile223=
Coding: c.669T>C
MANE Select: NM_001927
dbSNP: rs75882680
Type: single nucleotide variant
Location: chr2:219420280 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 223: the if rod domain; the 'coil 1b' 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

Also linked: cardiomyopathy neurogenic scapuloperoneal syndrome, Kaeser type dilated cardiomyopathy 1I

For Desminopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy

Similar variants

DES p.Ile223Val Uncertain significance ★ ⚠ same residue
DES p.Ile223Phe Uncertain significance ★ ⚠ same residue
DES p.Ile223Thr Uncertain significance ★ ⚠ 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

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-ile223 (accessed [today's date]).

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