Is DES p.Ser72Arg (c.216C>A) pathogenic?

DES p.Ser72Arg (c.216C>A) is classified Conflicting classifications of pathogenicity in DES (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-02-01). AlphaMissense: ambiguous (0.5471); Rare (popmax 0.201%, mid); Associated with Cardiovascular phenotype.

What condition is associated with DES p.Ser72Arg (c.216C>A)?

DES p.Ser72Arg (c.216C>A) is associated with Cardiovascular phenotype, cardiomyopathy, neurogenic scapuloperoneal syndrome, Kaeser type (ClinVar).

How common is DES p.Ser72Arg (c.216C>A) in the general population?

DES p.Ser72Arg (c.216C>A) is rare (popmax 0.201%, mid) (gnomAD).

What do computational predictors say about DES p.Ser72Arg (c.216C>A)?

AlphaMissense predicts ambiguous (score 0.5471) — an in-silico prediction, not a clinical call.

DES p.Ser72Arg

c.216C>A · rs375719734 · VCV193219

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

ambiguous

0.5471 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.201%, mid)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5471	ambiguous
REVEL	0.438	indeterminate
SaProt	LLR -8.58	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 0.73, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	23.0	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 0.201% Middle Eastern · 12/5,966 alleles

Filtering AF 0.116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.091%

Overall 0.0078% 123/1,577,254 alleles · rare exomes 108/1,425,032 · genomes 15/152,222 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.201%	497
Admixed American	0.0333%	3,000
South Asian	0.0311%	3,210
Remaining individualsnot grpmax-eligible	0.00982%	10,187
African / African-American	0.00804%	12,431
European (non-Finnish)	0.00465%	21,514

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.Ser72Arg
Coding: c.216C>A
MANE Select: NM_001927
dbSNP: rs375719734
Type: single nucleotide variant
Location: chr2:219418678 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 72: 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: cardiomyopathy neurogenic scapuloperoneal syndrome, Kaeser type myofibrillar myopathy 1 dilated cardiomyopathy 1I

Similar variants

DES p.Ser72Cys 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
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-ser72arg (accessed [today's date]).

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