Is DES p.Leu338= (c.1014G>C) pathogenic?

DES p.Leu338= (c.1014G>C) is classified Benign in DES (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-02-04). Common (popmax 44.6%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with DES p.Leu338= (c.1014G>C)?

DES p.Leu338= (c.1014G>C) is associated with Cardiovascular phenotype, neurogenic scapuloperoneal syndrome, Kaeser type, myofibrillar myopathy 1 (ClinVar).

DES p.Leu338=

Q: How common is DES p.Leu338= (c.1014G>C) in the general population?

DES p.Leu338= (c.1014G>C) is common (popmax 44.6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1014G>C · rs12920 · VCV44242

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

gnomAD v4.1

Common

common (popmax 44.6%, afr) — too common for a highly-penetrant pathogenic allele

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 1.1	GERP -2.1, phastCons 1
Overall
CADD	11.44	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 44.6% African / African-American · 33,358/74,866 alleles

Filtering AF 44.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 44%

Overall 34.4% 554,883/1,612,460 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	44.6%	2
Amishnot grpmax-eligible	43.6%	2
Middle Eastern	42.8%	2
Ashkenazi Jewishnot grpmax-eligible	41.5%	2
Remaining individualsnot grpmax-eligible	35.3%	3
European (non-Finnish)	34.9%	3
Admixed American	32.9%	3
South Asian	29.6%	3
Finnishnot grpmax-eligible	27.4%	4
East Asian	18.3%	5

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.Leu338=
Coding: c.1014G>C
MANE Select: NM_001927
dbSNP: rs12920
Type: single nucleotide variant
Location: chr2:219420944 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neurogenic scapuloperoneal syndrome, Kaeser type myofibrillar myopathy 1 dilated cardiomyopathy 1I

Similar variants

DES p.Leu338Pro Likely pathogenic ★ 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-leu338 (accessed [today's date]).

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