Is DES p.Leu190Pro (c.569T>C) pathogenic?

DES p.Leu190Pro (c.569T>C) is classified Conflicting classifications of pathogenicity in DES (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-28). AlphaMissense: likely pathogenic (0.9967); Absent from gnomAD v4.1; Associated with limb-girdle muscular dystrophy.

What condition is associated with DES p.Leu190Pro (c.569T>C)?

DES p.Leu190Pro (c.569T>C) is associated with limb-girdle muscular dystrophy, myofibrillar myopathy 1 (ClinVar).

How common is DES p.Leu190Pro (c.569T>C) in the general population?

DES p.Leu190Pro (c.569T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DES p.Leu190Pro (c.569T>C)?

AlphaMissense predicts likely pathogenic (score 0.9967) — an in-silico prediction, not a clinical call.

DES p.Leu190Pro

c.569T>C · VCV4011011

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9967 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

limb-girdle muscular dystrophy

Computational evidence

Protein change
AlphaMissense	0.9967	likely pathogenic · top 5% in DES
REVEL	0.845	moderately pathogenic-leaning
SaProt	LLR -14.55	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.74, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DES
Protein: p.Leu190Pro
Coding: c.569T>C
MANE Select: NM_001927
Type: single nucleotide variant
Location: chr2:219419031 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 190: the if rod domain; the 'coil 1b' region

Full DES gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

limb-girdle muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: myofibrillar myopathy 1

Similar variants

DES p.Leu190= Likely benign ★ same residue
DES p.Leu190fs Pathogenic ★ 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-leu190pro (accessed [today's date]).

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