Is DES p.Ala337Thr (c.1009G>A) pathogenic?

DES p.Ala337Thr (c.1009G>A) is classified Uncertain significance in DES (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). AlphaMissense: ambiguous (0.4238); Ultra-rare (popmax 0.0341%, sas); Associated with Cardiovascular phenotype.

What condition is associated with DES p.Ala337Thr (c.1009G>A)?

DES p.Ala337Thr (c.1009G>A) is associated with Cardiovascular phenotype, neurogenic scapuloperoneal syndrome, Kaeser type, myofibrillar myopathy 1 (ClinVar).

How common is DES p.Ala337Thr (c.1009G>A) in the general population?

DES p.Ala337Thr (c.1009G>A) is ultra-rare (popmax 0.0341%, sas) (gnomAD).

What do computational predictors say about DES p.Ala337Thr (c.1009G>A)?

AlphaMissense predicts ambiguous (score 0.4238) — an in-silico prediction, not a clinical call.

DES p.Ala337Thr

c.1009G>A · rs59962885 · VCV382176

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4238 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0341%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4238	ambiguous
REVEL	0.632	indeterminate
SaProt	LLR -8.16	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	32.0	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 0.0341% South Asian · 31/91,028 alleles

Filtering AF 0.0246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00359% 58/1,613,398 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0341%	2,936
African / African-American	0.0107%	9,362
Remaining individualsnot grpmax-eligible	0.0032%	31,229
East Asian	0.00223%	44,850
European (non-Finnish)	0.00136%	73,741

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.Ala337Thr
Coding: c.1009G>A
MANE Select: NM_001927
dbSNP: rs59962885
Type: single nucleotide variant
Location: chr2:219420939 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 337: the 'coil 2b' region; the if rod domain; a UniProt-annotated variant site (in mfm1; mild adult-onset; unable to form a functional filamentous network); 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.Ala337Asp Uncertain significance ★★ ⚠ same residue
DES p.Ala337Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
DES p.Ala337Ser Uncertain significance ★ ⚠ same residue
DES p.Ala337= Likely benign ★ 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-ala337thr (accessed [today's date]).

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