Is DES p.Arg189Trp (c.565C>T) pathogenic?

DES p.Arg189Trp (c.565C>T) is classified Uncertain significance in DES (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-12-04). AlphaMissense: ambiguous (0.4234); Very rare (popmax 0.00244%, eas); Associated with myofibrillar myopathy 1.

What condition is associated with DES p.Arg189Trp (c.565C>T)?

DES p.Arg189Trp (c.565C>T) is associated with myofibrillar myopathy 1 (ClinVar).

How common is DES p.Arg189Trp (c.565C>T) in the general population?

DES p.Arg189Trp (c.565C>T) is very rare (popmax 0.00244%, eas) (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.Arg189Trp (c.565C>T)?

AlphaMissense predicts ambiguous (score 0.4234) — an in-silico prediction, not a clinical call.

DES p.Arg189Trp

c.565C>T · rs1223277151 · VCV577606

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4234 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00244%, eas)

Conditions

myofibrillar myopathy 1

Computational evidence

Protein change
AlphaMissense	0.4234	ambiguous
REVEL	0.553	indeterminate
SaProt	LLR -14.96	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.88	GERP -3.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	26.8	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 0.00244% East Asian · 1/40,918 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000195% 3/1,541,930 alleles · very rare exomes 2/1,389,786 · genomes 1/152,144 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00244%	40,918
European (non-Finnish)	0.000174%	573,513

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.Arg189Trp
Coding: c.565C>T
MANE Select: NM_001927
dbSNP: rs1223277151
Type: single nucleotide variant
Location: chr2:219419027 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 189: the if rod domain; the 'coil 1b' 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.Arg189Gln Uncertain significance ★★ ⚠ same residue
DES p.Arg189= 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
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-arg189trp (accessed [today's date]).

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