Is DES p.Ser57Leu (c.170C>T) pathogenic?

DES p.Ser57Leu (c.170C>T) is classified Conflicting classifications of pathogenicity in DES (ClinVar, Conflicting submitters, 16 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.3074); Rare (popmax 0.133%, amr); Associated with Cardiovascular phenotype.

What condition is associated with DES p.Ser57Leu (c.170C>T)?

DES p.Ser57Leu (c.170C>T) is associated with Cardiovascular phenotype, neurogenic scapuloperoneal syndrome, Kaeser type, myofibrillar myopathy 1 (ClinVar).

How common is DES p.Ser57Leu (c.170C>T) in the general population?

DES p.Ser57Leu (c.170C>T) is rare (popmax 0.133%, amr) (gnomAD).

What do computational predictors say about DES p.Ser57Leu (c.170C>T)?

AlphaMissense predicts likely benign (score 0.3074) — an in-silico prediction, not a clinical call.

DES p.Ser57Leu

c.170C>T · rs372825868 · VCV44254

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.3074 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.133%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3074	likely benign
REVEL	0.566	indeterminate
SaProt	LLR -11.20	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 0.58, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	25.0	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 0.133% Admixed American · 78/58,434 alleles

Filtering AF 0.11% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.101%

Overall 0.0178% 284/1,599,882 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.133%	749
African / African-American	0.128%	779
Middle Eastern	0.0832%	1,202
Remaining individualsnot grpmax-eligible	0.0631%	1,585
Ashkenazi Jewishnot grpmax-eligible	0.0345%	2,895
European (non-Finnish)	0.00477%	20,959

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.Ser57Leu
Coding: c.170C>T
MANE Select: NM_001927
dbSNP: rs372825868
Type: single nucleotide variant
Location: chr2:219418632 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 57: 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: neurogenic scapuloperoneal syndrome, Kaeser type myofibrillar myopathy 1 dilated cardiomyopathy 1I

Similar variants

DES p.Ser57= 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
DES p.Ala285Val 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-ser57leu (accessed [today's date]).

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