Is DES p.Ser298Leu (c.893C>T) pathogenic?

DES p.Ser298Leu (c.893C>T) is classified Conflicting classifications of pathogenicity in DES (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-01-28). AlphaMissense: ambiguous (0.5321); Ultra-rare (popmax 0.0225%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with DES p.Ser298Leu (c.893C>T)?

DES p.Ser298Leu (c.893C>T) is associated with Cardiovascular phenotype, cardiomyopathy, dilated cardiomyopathy (ClinVar).

How common is DES p.Ser298Leu (c.893C>T) in the general population?

DES p.Ser298Leu (c.893C>T) is ultra-rare (popmax 0.0225%, nfe) (gnomAD).

What do computational predictors say about DES p.Ser298Leu (c.893C>T)?

AlphaMissense predicts ambiguous (score 0.5321) — an in-silico prediction, not a clinical call.

DES p.Ser298Leu

c.893C>T · rs62636491 · VCV66423

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

ambiguous

0.5321 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0225%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5321	ambiguous
REVEL	0.814	moderately pathogenic-leaning
SaProt	LLR -9.44	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	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 0.0225% European (non-Finnish) · 266/1,180,022 alleles

Filtering AF 0.0203% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0194%

Overall 0.0178% 287/1,613,856 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0225%	4,436
Middle Eastern	0.0164%	6,082
African / African-American	0.0147%	6,807
Remaining individualsnot grpmax-eligible	0.0112%	8,926
Admixed American	0.00333%	29,993

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.Ser298Leu
Coding: c.893C>T
MANE Select: NM_001927
dbSNP: rs62636491
Type: single nucleotide variant
Location: chr2:219420652 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 298: the 'coil 2b' region; the if rod domain; 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: cardiomyopathy dilated cardiomyopathy neurogenic scapuloperoneal syndrome, Kaeser type myofibrillar myopathy 1 dilated cardiomyopathy 1I

Similar variants

DES p.Ser298= Likely benign ★★ same residue
DES p.Ser298Thr 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
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-ser298leu (accessed [today's date]).

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