Is DES p.Leu274= (c.822C>T) pathogenic?

DES p.Leu274= (c.822C>T) is classified Conflicting classifications of pathogenicity in DES (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-21). Very rare (popmax 0.00267%, afr); Associated with Cardiovascular phenotype.

What condition is associated with DES p.Leu274= (c.822C>T)?

DES p.Leu274= (c.822C>T) is associated with Cardiovascular phenotype, myofibrillar myopathy 1 (ClinVar).

How common is DES p.Leu274= (c.822C>T) in the general population?

DES p.Leu274= (c.822C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

DES p.Leu274=

c.822C>T · rs763599850 · VCV285097

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.85	GERP -3.7, phastCons 1
Overall
CADD	15.06	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,870 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,613,894 alleles · very rare exomes 3/1,461,814 · genomes 1/152,080 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,435
European (non-Finnish)	0.000169%	590,005

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.Leu274=
Coding: c.822C>T
MANE Select: NM_001927
dbSNP: rs763599850
Type: single nucleotide variant
Location: chr2:219420581 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 274: the if rod domain; the 'interaction with neb' region; the 'coil 2a' 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: myofibrillar myopathy 1

Similar variants

DES p.Leu274His Likely pathogenic ★ same residue
DES p.Leu274Pro Likely pathogenic ★ same residue
DES p.Leu274Arg Conflicting classifications of pathogenicity ★ ⚠ 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-leu274 (accessed [today's date]).

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