Is DES p.Pro33= (c.99C>T) pathogenic?

DES p.Pro33= (c.99C>T) is classified Benign/Likely benign in DES (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-14). Ultra-rare (popmax 0.0166%, mid); Associated with Cardiovascular phenotype.

What condition is associated with DES p.Pro33= (c.99C>T)?

DES p.Pro33= (c.99C>T) is associated with Cardiovascular phenotype, cardiomyopathy, myofibrillar myopathy 1 (ClinVar).

How common is DES p.Pro33= (c.99C>T) in the general population?

DES p.Pro33= (c.99C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

DES p.Pro33=

c.99C>T · rs774006810 · VCV227284

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP -3
Overall
CADD	10.28	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,032 alleles

Filtering AF 0.00658% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0061%

Overall 0.00667% 107/1,603,418 alleles · ultra-rare exomes 99/1,451,312 · genomes 8/152,106 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,032
Remaining individualsnot grpmax-eligible	0.0129%	7,735
European (non-Finnish)	0.00791%	12,643
Finnishnot grpmax-eligible	0.00645%	15,508
African / African-American	0.00134%	74,476

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.Pro33=
Coding: c.99C>T
MANE Select: NM_001927
dbSNP: rs774006810
Type: single nucleotide variant
Location: chr2:219418561 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 33: 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 myofibrillar myopathy 1

Similar variants

DES p.Pro33Ser 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-pro33 (accessed [today's date]).

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