Is DES p.Pro419= (c.1257C>T) pathogenic?

DES p.Pro419= (c.1257C>T) is classified Conflicting classifications of pathogenicity in DES (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-22). Ultra-rare (popmax 0.0334%, afr); Associated with Cardiovascular phenotype.

What condition is associated with DES p.Pro419= (c.1257C>T)?

DES p.Pro419= (c.1257C>T) is associated with Cardiovascular phenotype, myofibrillar myopathy 1 (ClinVar).

How common is DES p.Pro419= (c.1257C>T) in the general population?

DES p.Pro419= (c.1257C>T) is ultra-rare (popmax 0.0334%, afr) (gnomAD).

DES p.Pro419=

c.1257C>T · rs143154982 · VCV384758

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, afr)

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 -1.8	GERP -3.7
Overall
CADD	1.455	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0334% African / African-American · 25/74,908 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0198%

Overall 0.00161% 26/1,613,766 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0334%	2,996
Remaining individualsnot grpmax-eligible	0.0016%	62,472

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.Pro419=
Coding: c.1257C>T
MANE Select: NM_001927
dbSNP: rs143154982
Type: single nucleotide variant
Location: chr2:219423789 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 419: the 'tail' region; a UniProt-annotated variant site (in mfm1; found in a family with myofibrillar myopathy and arrhythmogenic right ventricular cardiomyopathy)

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.Pro419Ser Pathogenic/Likely pathogenic ★★ ⚠ same residue
DES p.Pro419Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
DES p.Pro419Thr Uncertain significance ★ ⚠ same residue
DES p.Pro419fs Pathogenic ★★ 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-pro419 (accessed [today's date]).

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