Is DES p.Leu345Pro (c.1034T>C) pathogenic?

DES p.Leu345Pro (c.1034T>C) is classified Pathogenic/Likely pathogenic in DES (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-06-04). AlphaMissense: likely pathogenic (0.9997); Absent from gnomAD v4.1; Associated with DES-related disorders.

What condition is associated with DES p.Leu345Pro (c.1034T>C)?

DES p.Leu345Pro (c.1034T>C) is associated with DES-related disorders, myofibrillar myopathy 1 (ClinVar).

How common is DES p.Leu345Pro (c.1034T>C) in the general population?

DES p.Leu345Pro (c.1034T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DES p.Leu345Pro (c.1034T>C)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

DES p.Leu345Pro

c.1034T>C · rs57639980 · VCV16825

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DES-related disorders

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic ✓ concordant with ClinVar · top 1% in DES
REVEL	0.982	strongly pathogenic-leaning
SaProt	LLR -15.46	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 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	33.0	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.Leu345Pro
Coding: c.1034T>C
MANE Select: NM_001927
dbSNP: rs57639980
Type: single nucleotide variant
Location: chr2:219421350 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 345: the 'coil 2b' region; the if rod domain; a UniProt-annotated variant site (in mfm1; distal onset; incapable of forming filamentous networks); the 'interaction with neb' region

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

Disease context

DES-related disorders

Also linked: myofibrillar myopathy 1

Similar variants

DES p.Leu345= Likely benign ★ same residue
DES p.Leu345fs Likely 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
DES c.735+3A>G Pathogenic ★★ same condition
DES c.736-1G>A 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-leu345pro (accessed [today's date]).

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