Legius syndrome (SPRED1) OMIM 611431

In Legius syndrome (SPRED1, OMIM 611431), the master switch sits on the ↑ UP branch ([F] forced below); the healthy state is the ON well. The forced corrective direction is to raise s toward ON branch (polarity: clear). Classification: ○ Novel direction-only lead. Direction only — no dose, no efficacy magnitude.

The disease maps to an R19 double-well whose corrective lever is read straight off the cusp (barrier 0.5935, γ 1.5408, spinodal 0.7362). The corrective direction is forced [F]; the agent names below are direction-concordant labels at grade [O] (no dose, no efficacy or safety magnitude). This is a research hypothesis offered to experts, not medical advice.

The emergence switch

The switch for Legius syndrome is an R19 double-well emerged from the real proximal-promoter DNA of SPRED1. Its geometry is fixed by measured stiffness γ (never fitted); the numbers below are read directly off that cusp.

emergent axis: ↑ UP [F]
healthy branch: ON
lesion: LOF_null
γ (stiffness): 1.5408
barrier: 0.5935
spinodal: 0.7362
s_on / s_off: 1.2413 / -1.2413
fragility: 0.03
corrective polarity: clear
forced direction: raise s toward ON branch

Chemistry feasibility (DIRECTION only [O]). small-molecule recrossing of the fold is geometrically harder (barrier 0.5935 at neutral drive; lower barrier = smaller drive to supply). [O] -- no affinity/potency/dose/efficacy asserted.

The derived corrective lever

The cusp forces a corrective direction: raise s toward ON branch. This is the load-bearing output of the framework — it is [F] forced, and it is falsifiable. 2 lever families are derived; the lead is h-restore (drive modulator).

h-restore (drive modulator)sign: decreasegeometric rank 0.03

Mechanism. remove / oppose the drive (clear the accumulating load that pins the disease branch)

Applies to. allele-agnostic (downstream/environmental tilt)

favoured when the switch is fragile -- a small drive shift recrosses the fold

Falsifier. If clearing/opposing the accumulating RAS-MAPK over-activation released by loss of the SPRED1 negative regulator does NOT relieve the disease branch in a SPRED1 model, the h-restore(clear) lever is refuted for this axis.

gamma-restore (stabiliser / chaperone)sign: Nonegeometric rank 0.00

Mechanism. N/A

Applies to. none (honest exclusion)

EXCLUDED: null allele -- no product to stiffen

Falsifier. If a folding-stabiliser/chaperone does NOT re-deepen the healthy well for a residual SPRED1 allele (no rescue that a null allele lacks), the gamma-restore lever is refuted; null alleles are excluded by construction.

Agents mapped onto the lever

Existing agents whose known action is direction-concordant with the derived lever (status as pinned in the corpus; no dose, no efficacy magnitude).
agent (class)	dir.	status	phase	map
MEK1/2 inhibition (selumetinib) opposing the RAS-MAPK over-activation released by SPRED1 loss Brems 2007 Nat Genet 39:1120	decrease	investigational (not approved for this indication)	0	◇ in trials

⚠ Mechanism-direction only — do not self-administer; no dose (unvalidated; set by a physician / national authority); not an approved use.

Direction-only candidate leads (corpus join)

Each lead is surfaced only because its known mechanism points the same way as the derived lever, and each comes with a source and a falsifier. None is a treatment.

selumetinib (MEK1/2 inhibition) [SPRED1 Legius]○ novel leaddir: decrease · investigational (not approved for this indication)

Class. MEK1/2 inhibitor (RAS-MAPK over-activation opposition)

Mechanism. Direction-concordant (decrease) agent for SPRED1; magnitude open [O]; direction-only repurposing/recovery signal, not a claim of efficacy or safety for any patient.

Prior-art. Selumetinib (an approved MEK inhibitor for NF1 plexiform neurofibromas) is direction-concordant with the RAS-MAPK over-activation of Legius syndrome; direction-only, not approved for this indication.

Safety (qualitative; no magnitude). established/known-use safety reporting on record (qualitative; no magnitude)

Falsifier. If selumetinib (MEK1/2 inhibition) [SPRED1 Legius] (a gene-specific decrease agent) clearing/opposing the accumulating load does NOT relieve the UP [F] disease branch in a SPRED1 model, the h-restore(clear) direction is refuted for selumetinib (MEK1/2 inhibition) [SPRED1 Legius] here.

Source: Brems 2007 Nat Genet 39:1120 (SPRED1 loss-of-function causes an NF1-like phenotype)

⚠ Mechanism-direction only — do not self-administer; no dose (unvalidated; set by a physician / national authority); not an approved use.

Evidence & provenance

What is reproduced vs. cited for this page.
element	grade	basis
R19 switch & cusp geometry (this page)	[V] verified	emerged from measured promoter γ of `SPRED1`; deterministic, 2×sha256 identical
corrective direction	[F] forced	forced by the cusp sign; falsifiable (see lever falsifiers)
mapped agents / leads	[O] open	direction-concordance only; corpus-pinned (2026-06-21); no dose, no efficacy/safety magnitude

Reading the agent column. VALIDATION SIGNAL -- the agent is already approved / established standard for this disease, so the direction logic recovered known clinical practice. Not a new claim by this kit. GENUINE HYPOTHESIS -- no approved indication for this disease; the direction match is a direction-only, untested [O] lead. Basis field grades the evidence (investigational here / in a related condition / off-label / speculative).