Is DES p.Arg415= (c.1245G>A) pathogenic?

DES p.Arg415= (c.1245G>A) is classified Conflicting classifications of pathogenicity in DES (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-03). Very rare (popmax 0.00134%, afr); Associated with myofibrillar myopathy 1.

What condition is associated with DES p.Arg415= (c.1245G>A)?

DES p.Arg415= (c.1245G>A) is associated with myofibrillar myopathy 1 (ClinVar).

How common is DES p.Arg415= (c.1245G>A) in the general population?

DES p.Arg415= (c.1245G>A) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Desminopathy inherited?

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

DES p.Arg415=

c.1245G>A · VCV3758290

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

myofibrillar myopathy 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.4	GERP -2.1, phastCons 1
Overall
CADD	12.85	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,894 alleles

Overall 0.000124% 2/1,613,716 alleles · very rare exomes 1/1,461,590 · genomes 1/152,126 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,894
European (non-Finnish)	8.48e-05%	1,179,837

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.Arg415=
Coding: c.1245G>A
MANE Select: NM_001927
Type: single nucleotide variant
Location: chr2:219423777 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 415: the 'tail' region; the if rod domain; the 'interaction with neb' 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

For Desminopathy (Orphanet):

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

Similar variants

DES p.Arg415Gln Uncertain significance ★★ ⚠ same residue
DES p.Arg415Gly Uncertain significance ★★ ⚠ same residue
DES p.Arg415Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
DES p.Arg415fs 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

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-arg415 (accessed [today's date]).

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