Is DES p.Leu338Pro (c.1013T>C) pathogenic?

DES p.Leu338Pro (c.1013T>C) is classified Likely pathogenic in DES (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-29). AlphaMissense: likely pathogenic (0.9994); Very rare (popmax 0.00133%, afr); Associated with myofibrillar myopathy 1.

What condition is associated with DES p.Leu338Pro (c.1013T>C)?

DES p.Leu338Pro (c.1013T>C) is associated with myofibrillar myopathy 1 (ClinVar).

How common is DES p.Leu338Pro (c.1013T>C) in the general population?

DES p.Leu338Pro (c.1013T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Desminopathy inherited?

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

What do computational predictors say about DES p.Leu338Pro (c.1013T>C)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

DES p.Leu338Pro

c.1013T>C · rs57496341 · VCV239071

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9994 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myofibrillar myopathy 1

Computational evidence

Protein change
AlphaMissense	0.9994	likely pathogenic ✓ concordant with ClinVar · top 1% in DES
REVEL	0.955	strongly pathogenic-leaning
SaProt	LLR -18.25	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 7.9	GERP 1.7, 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

Grpmax group 0.00133% African / African-American · 1/75,026 alleles

Overall 6.84e-05% 1/1,461,270 alleles · very rare

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.Leu338Pro
Coding: c.1013T>C
MANE Select: NM_001927
dbSNP: rs57496341
Type: single nucleotide variant
Location: chr2:219420943 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 338: the 'coil 2b' region; the if rod domain; a UniProt-annotated variant site (in mfm1; results in the formation of a filamentous network disrupted by multiple breaks and clumps or large aggregates); 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.Leu338= Benign ★★ same residue
DES p.Leu338Arg 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 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-leu338pro (accessed [today's date]).

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