Is DES p.Arg173Ser (c.517C>A) pathogenic?

DES p.Arg173Ser (c.517C>A) is classified Uncertain significance in DES (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-11). AlphaMissense: likely pathogenic (0.8161); Very rare (popmax 0.00273%, afr); Associated with Cardiovascular phenotype.

What condition is associated with DES p.Arg173Ser (c.517C>A)?

DES p.Arg173Ser (c.517C>A) is associated with Cardiovascular phenotype, neurogenic scapuloperoneal syndrome, Kaeser type, myofibrillar myopathy 1 (ClinVar).

How common is DES p.Arg173Ser (c.517C>A) in the general population?

DES p.Arg173Ser (c.517C>A) is very rare (popmax 0.00273%, afr) (gnomAD).

What do computational predictors say about DES p.Arg173Ser (c.517C>A)?

AlphaMissense predicts likely pathogenic (score 0.8161) — an in-silico prediction, not a clinical call.

DES p.Arg173Ser

c.517C>A · rs752944882 · VCV1011900

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8161 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00273%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.8161	likely pathogenic
REVEL	0.756	pathogenic-leaning
SaProt	LLR -11.58	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP -3.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00273% African / African-American · 2/73,178 alleles

Filtering AF 0.000454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000217%

Overall 0.000645% 10/1,550,390 alleles · very rare exomes 8/1,398,252 · genomes 2/152,138 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00273%	36,589
European (non-Finnish)	0.000697%	143,465

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.Arg173Ser
Coding: c.517C>A
MANE Select: NM_001927
dbSNP: rs752944882
Type: single nucleotide variant
Location: chr2:219418979 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 173: the if rod domain; a UniProt-annotated variant site (in mfm1; severe form); the 'coil 1b' 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.Arg173= Likely benign ★★ same residue
DES p.Arg173Gly Uncertain significance ★ ⚠ same residue
DES p.Arg173His 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-arg173ser (accessed [today's date]).

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