Is DSE p.Ala135= (c.405G>A) pathogenic?

DSE p.Ala135= (c.405G>A) is classified Likely benign in DSE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-13). Very rare (popmax 0.00501%, amr); Associated with Ehlers-Danlos syndrome, musculocontractural type 2.

What condition is associated with DSE p.Ala135= (c.405G>A)?

DSE p.Ala135= (c.405G>A) is associated with Ehlers-Danlos syndrome, musculocontractural type 2 (ClinVar).

How common is DSE p.Ala135= (c.405G>A) in the general population?

DSE p.Ala135= (c.405G>A) is very rare (popmax 0.00501%, amr) (gnomAD).

How is Musculocontractural Ehlers-Danlos syndrome inherited?

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

DSE p.Ala135=

c.405G>A · VCV4695861

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

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	phastCons 1
Overall
CADD	12.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00501% Admixed American · 3/59,928 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00136% 22/1,612,596 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00501%	19,976
South Asian	0.0033%	30,329
African / African-American	0.00267%	37,457
Remaining individualsnot grpmax-eligible	0.0016%	62,418
European (non-Finnish)	0.0011%	90,691

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.Ala135=
Coding: c.405G>A
MANE Select: NM_013352
Type: single nucleotide variant
Location: chr6:116399655 (GRCh38)
Gene constraint: LOEUF 0.563 · pLI 0.06 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.59 · 1 PDB

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 p.Ala135Val Uncertain significance ★★ ⚠ same residue
TSPYL1 p.Cys135= Uncertain significance ★ same residue
TSPYL1 p.Cys135Arg Uncertain significance ★ ⚠ same residue
DSE c.416+1G>A Likely pathogenic ★★ same condition
DSE p.Ala122Thr 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

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-ala135 (accessed [today's date]).

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