Is DES p.Glu100Ala (c.299A>C) pathogenic?

DES p.Glu100Ala (c.299A>C) is classified Conflicting classifications of pathogenicity in DES (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-18). AlphaMissense: ambiguous (0.5458); Very rare (popmax 0.00191%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with DES p.Glu100Ala (c.299A>C)?

DES p.Glu100Ala (c.299A>C) is associated with Cardiovascular phenotype, myofibrillar myopathy 1, dilated cardiomyopathy 1I (ClinVar).

How common is DES p.Glu100Ala (c.299A>C) in the general population?

DES p.Glu100Ala (c.299A>C) is very rare (popmax 0.00191%, nfe) (gnomAD).

What do computational predictors say about DES p.Glu100Ala (c.299A>C)?

AlphaMissense predicts ambiguous (score 0.5458) — an in-silico prediction, not a clinical call.

DES p.Glu100Ala

c.299A>C · rs762738069 · VCV201719

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.5458 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00191%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5458	ambiguous
REVEL	0.776	moderately pathogenic-leaning
SaProt	LLR -11.02	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 0.93, 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 0.00191% European (non-Finnish) · 22/1,152,880 alleles

Filtering AF 0.00125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00107%

Overall 0.00147% 23/1,562,532 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00191%	52,404
Remaining individualsnot grpmax-eligible	0.00165%	60,566

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.Glu100Ala
Coding: c.299A>C
MANE Select: NM_001927
dbSNP: rs762738069
Type: single nucleotide variant
Location: chr2:219418761 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 100: the 'head' 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: myofibrillar myopathy 1 dilated cardiomyopathy 1I

Similar variants

DES p.Glu100Gly Uncertain significance ★★ ⚠ same residue
DES p.Glu100= Conflicting classifications of pathogenicity ★ same residue
DES p.Glu100Lys Uncertain significance ★ ⚠ 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

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-glu100ala (accessed [today's date]).

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