Is DSE p.Leu140Phe (c.420G>C) pathogenic?

DSE p.Leu140Phe (c.420G>C) is classified Uncertain significance in DSE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-09). AlphaMissense: ambiguous (0.5208); Absent from gnomAD v4.1; Associated with Ehlers-Danlos syndrome, musculocontractural type 2.

What condition is associated with DSE p.Leu140Phe (c.420G>C)?

DSE p.Leu140Phe (c.420G>C) is associated with Ehlers-Danlos syndrome, musculocontractural type 2 (ClinVar).

How common is DSE p.Leu140Phe (c.420G>C) in the general population?

DSE p.Leu140Phe (c.420G>C) is absent from gnomAD v4.1 (gnomAD).

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.Leu140Phe (c.420G>C)?

AlphaMissense predicts ambiguous (score 0.5208) — an in-silico prediction, not a clinical call.

DSE p.Leu140Phe

c.420G>C · rs2482242741 · VCV2046992

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5208 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Ehlers-Danlos syndrome, musculocontractural type 2

Computational evidence

Protein change
AlphaMissense	0.5208	ambiguous
REVEL	0.196	benign-leaning
SaProt	LLR -7.41	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 36 kb · p 6.1e-20 · regional, not allelic
Overall
CADD	22.1	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: DSE
Protein: p.Leu140Phe
Coding: c.420G>C
MANE Select: NM_013352
dbSNP: rs2482242741
Type: single nucleotide variant
Location: chr6:116426577 (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.Leu140= Uncertain significance ★ same residue
TSPYL1 p.Ser140= 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-leu140phe (accessed [today's date]).

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