Is DSE p.Pro34Leu (c.101C>T) pathogenic?

DSE p.Pro34Leu (c.101C>T) is classified Benign/Likely benign in DSE (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1687); Common (popmax 6.67%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Ehlers-Danlos syndrome, musculocontractural type 2.

What condition is associated with DSE p.Pro34Leu (c.101C>T)?

DSE p.Pro34Leu (c.101C>T) is associated with Ehlers-Danlos syndrome, musculocontractural type 2 (ClinVar).

How is Musculocontractural Ehlers-Danlos syndrome inherited?

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

What do computational predictors say about DSE p.Pro34Leu (c.101C>T)?

AlphaMissense predicts likely benign (score 0.1687) — an in-silico prediction, not a clinical call.

DSE p.Pro34Leu

Q: How common is DSE p.Pro34Leu (c.101C>T) in the general population?

DSE p.Pro34Leu (c.101C>T) is common (popmax 6.67%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.101C>T · rs35548455 · VCV384700

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1687 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.67%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ehlers-Danlos syndrome, musculocontractural type 2

Computational evidence

Protein change
AlphaMissense	0.1687	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -8.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 117 bp · p 0.73 · regional, not allelic
Overall
CADD	25.5	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

Grpmax group 6.67% European (non-Finnish) · 78,765/1,180,018 alleles

Filtering AF 6.64% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.62%

Overall 5.73% 92,444/1,614,064 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	6.67%	15
Ashkenazi Jewishnot grpmax-eligible	5.84%	17
Remaining individualsnot grpmax-eligible	5.72%	17
Middle Eastern	4.72%	21
Amishnot grpmax-eligible	4.5%	22
South Asian	3.68%	27
Admixed American	3.44%	29
Finnishnot grpmax-eligible	2.78%	36
African / African-American	1.12%	89
East Asian	0.0156%	6,411

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.Pro34Leu
Coding: c.101C>T
MANE Select: NM_013352
dbSNP: rs35548455
Type: single nucleotide variant
Location: chr6:116399351 (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 34: a UniProt-annotated variant site (in)

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.Pro34Arg Uncertain significance ★★ ⚠ same residue
DSE p.Pro34= Likely benign ★ same residue
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

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-pro34leu (accessed [today's date]).

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