Is DES p.Pro22Arg (c.65C>G) pathogenic?

DES p.Pro22Arg (c.65C>G) is classified Uncertain significance in DES (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.1776); Ultra-rare (popmax 0.0159%, eas); Associated with Cardiovascular phenotype.

What condition is associated with DES p.Pro22Arg (c.65C>G)?

DES p.Pro22Arg (c.65C>G) is associated with Cardiovascular phenotype, neurogenic scapuloperoneal syndrome, Kaeser type, myofibrillar myopathy 1 (ClinVar).

How common is DES p.Pro22Arg (c.65C>G) in the general population?

DES p.Pro22Arg (c.65C>G) is ultra-rare (popmax 0.0159%, eas) (gnomAD).

What do computational predictors say about DES p.Pro22Arg (c.65C>G)?

AlphaMissense predicts likely benign (score 0.1776) — an in-silico prediction, not a clinical call.

DES p.Pro22Arg

c.65C>G · rs748158450 · VCV660762

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1776 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0159%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1776	likely benign
REVEL	0.285	benign-leaning
SaProt	LLR -8.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.23, phastCons 0.9
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	17.48	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0159% East Asian · 7/43,924 alleles

Filtering AF 0.0074% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00524%

Overall 0.000748% 12/1,603,646 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0159%	6,275
South Asian	0.00222%	45,075
Remaining individualsnot grpmax-eligible	0.00161%	61,964
European (non-Finnish)	0.00017%	588,221

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.Pro22Arg
Coding: c.65C>G
MANE Select: NM_001927
dbSNP: rs748158450
Type: single nucleotide variant
Location: chr2:219418527 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 22: 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.Pro22= Likely benign ★★ same residue
DES p.Pro22Leu 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

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-pro22arg (accessed [today's date]).

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