Is DES p.Ala213= (c.639G>A) pathogenic?

DES p.Ala213= (c.639G>A) is classified Uncertain significance in DES (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-11). Ultra-rare (popmax 0.0593%, sas); Associated with Cardiovascular phenotype.

What condition is associated with DES p.Ala213= (c.639G>A)?

DES p.Ala213= (c.639G>A) is associated with Cardiovascular phenotype, myofibrillar myopathy 1 (ClinVar).

How common is DES p.Ala213= (c.639G>A) in the general population?

DES p.Ala213= (c.639G>A) is ultra-rare (popmax 0.0593%, sas) (gnomAD).

DES p.Ala213=

c.639G>A · rs377337947 · VCV474290

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0593%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.71	GERP -0.78, phastCons 1
Overall
CADD	20.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0593% South Asian · 54/91,090 alleles

Filtering AF 0.0466% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0421%

Overall 0.00496% 80/1,614,104 alleles · ultra-rare exomes 73/1,461,890 · genomes 7/152,214 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0593%	1,687
Middle Eastern	0.0164%	6,084
Admixed American	0.005%	20,004
Remaining individualsnot grpmax-eligible	0.0032%	31,245
European (non-Finnish)	0.00161%	62,107
African / African-American	0.00133%	74,936

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.Ala213=
Coding: c.639G>A
MANE Select: NM_001927
dbSNP: rs377337947
Type: single nucleotide variant
Location: chr2:219420155 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 213: the if rod domain; a UniProt-annotated variant site (may play a role in cardiomyopathies and distal myopathies if combined with other des mutations or mutations in other genes; does not affect the formation of a normal complete filamentous network); the 'coil 1b' region

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

Similar variants

DES p.Ala213Thr Uncertain significance ★★ ⚠ same residue
DES p.Ala213Val 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

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-ala213 (accessed [today's date]).

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