Is DSE p.Gln227= (c.681A>G) pathogenic?

DSE p.Gln227= (c.681A>G) is classified Likely benign in DSE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-08). Ultra-rare (popmax 0.0898%, mid); Associated with Ehlers-Danlos syndrome, musculocontractural type 2.

What condition is associated with DSE p.Gln227= (c.681A>G)?

DSE p.Gln227= (c.681A>G) is associated with Ehlers-Danlos syndrome, musculocontractural type 2 (ClinVar).

How common is DSE p.Gln227= (c.681A>G) in the general population?

DSE p.Gln227= (c.681A>G) is ultra-rare (popmax 0.0898%, mid) (gnomAD).

How is Musculocontractural Ehlers-Danlos syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

DSE p.Gln227=

c.681A>G · rs754860828 · VCV2083474

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0898%, mid)

Conditions

Ehlers-Danlos syndrome, musculocontractural type 2

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 -2.1	GERP -4.5
Overall
CADD	3.52	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0898% Middle Eastern · 5/5,566 alleles

Filtering AF 0.0353% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0229%

Overall 0.00353% 57/1,613,414 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0898%	1,113
Remaining individualsnot grpmax-eligible	0.00961%	10,404
East Asian	0.00445%	22,447
European (non-Finnish)	0.00347%	28,781
Finnishnot grpmax-eligible	0.00156%	64,022
African / African-American	0.00133%	74,928
South Asian	0.0011%	91,048

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: DSE
Protein: p.Gln227=
Coding: c.681A>G
MANE Select: NM_013352
dbSNP: rs754860828
Type: single nucleotide variant
Location: chr6:116430964 (GRCh38)
Gene constraint: LOEUF 0.563 · pLI 0.06 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.59 · 1 PDB
Residue 227: an α-helix

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

Disease context

Ehlers-Danlos syndrome, musculocontractural type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Musculocontractural Ehlers-Danlos syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

DSE c.416+1G>A Likely pathogenic ★★ same condition
DSE p.Ala122Thr Uncertain significance ★★ ⚠ same condition
DSE p.Ala135Val Uncertain significance ★★ ⚠ same condition
DSE p.Ala408Thr Uncertain significance ★★ ⚠ same condition
DSE p.Ala54Val Uncertain significance ★★ ⚠ same condition
DSE p.Ala584Val Uncertain significance ★★ ⚠ same condition
DSE p.Ala688Val Uncertain significance ★★ ⚠ same condition
DSE p.Ala710Val Uncertain significance ★★ ⚠ 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/dse-p-gln227 (accessed [today's date]).

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