Is DES p.Ser6Trp (c.17C>G) pathogenic?

DES p.Ser6Trp (c.17C>G) is classified Conflicting classifications of pathogenicity in DES (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-01-23). AlphaMissense: ambiguous (0.5391); Very rare (popmax 8.5e-05%, nfe); Associated with myofibrillar myopathy 1.

What condition is associated with DES p.Ser6Trp (c.17C>G)?

DES p.Ser6Trp (c.17C>G) is associated with myofibrillar myopathy 1 (ClinVar).

How common is DES p.Ser6Trp (c.17C>G) in the general population?

DES p.Ser6Trp (c.17C>G) is very rare (popmax 8.5e-05%, nfe) (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.Ser6Trp (c.17C>G)?

AlphaMissense predicts ambiguous (score 0.5391) — an in-silico prediction, not a clinical call.

DES p.Ser6Trp

c.17C>G · rs1214936508 · VCV1436615

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5391 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

myofibrillar myopathy 1

Computational evidence

Protein change
AlphaMissense	0.5391	ambiguous
REVEL	0.815	moderately pathogenic-leaning
SaProt	LLR -11.44	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 5.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	27.7	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 8.5e-05% European (non-Finnish) · 1/1,177,012 alleles

Overall 6.91e-05% 1/1,446,182 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.Ser6Trp
Coding: c.17C>G
MANE Select: NM_001927
dbSNP: rs1214936508
Type: single nucleotide variant
Location: chr2:219418479 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 6: the 'head' 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.Ser6Leu Uncertain significance ★★ ⚠ same residue
DES p.Ser6= Conflicting classifications of pathogenicity ★ 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-ser6trp (accessed [today's date]).

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