Is DES p.Ala357Pro (c.1069G>C) pathogenic?

DES p.Ala357Pro (c.1069G>C) is classified Pathogenic in DES (ClinVar, Single submitter, 3 submitters; last evaluated 2017-07-27). AlphaMissense: likely pathogenic (0.9632); Absent from gnomAD v4.1; Associated with myofibrillar myopathy.

What condition is associated with DES p.Ala357Pro (c.1069G>C)?

DES p.Ala357Pro (c.1069G>C) is associated with myofibrillar myopathy (ClinVar).

How common is DES p.Ala357Pro (c.1069G>C) in the general population?

DES p.Ala357Pro (c.1069G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DES p.Ala357Pro (c.1069G>C)?

AlphaMissense predicts likely pathogenic (score 0.9632) — an in-silico prediction, not a clinical call.

DES p.Ala357Pro

c.1069G>C · rs58898021 · VCV66390

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9632 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myofibrillar myopathy

Computational evidence

Protein change
AlphaMissense	0.9632	likely pathogenic ✓ concordant with ClinVar
REVEL	0.726	pathogenic-leaning
SaProt	LLR -11.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP -0.46, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	26.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DES
Protein: p.Ala357Pro
Coding: c.1069G>C
MANE Select: NM_001927
dbSNP: rs58898021
Type: single nucleotide variant
Location: chr2:219421385 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 357: the 'coil 2b' region; the if rod domain; a UniProt-annotated variant site (in mfm1; unable to polymerize and form an intracellular filamentous network; abolishes binding to mtm1); the 'interaction with neb' region

Full DES gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

myofibrillar myopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DES p.Lys449Thr Pathogenic/Likely pathogenic ★★ same condition
DES c.735+20C>T Benign ★★ same condition
DES p.Ala213Val Conflicting classifications of pathogenicity ★ ⚠ same condition
DES p.Arg16Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
DES c.1289-2A>G Pathogenic/Likely pathogenic ★★ same type
DES c.579-2A>C Likely pathogenic ★★ same type
DES c.735+1G>A Pathogenic/Likely pathogenic ★★ same type
DES c.735+1G>C Pathogenic/Likely pathogenic ★★ same type

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-ala357pro (accessed [today's date]).

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