In Activated PI3K-delta syndrome 1 (PIK3CD, OMIM 615513), the master switch sits on the ↑ UP branch ([F] forced below); the healthy state is the OFF well. The forced corrective direction is to lower s toward OFF branch (polarity: clear). Classification: ✓ Recovers an existing standard. 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 0.5555, γ 1.4907, spinodal 0.7005). 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 Activated PI3K-delta syndrome 1 is an R19 double-well emerged from the real proximal-promoter DNA of PIK3CD. 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
OFF
lesion
GOF
γ (stiffness)
1.4907
barrier
0.5555
spinodal
0.7005
s_on / s_off
1.2209 / -1.2209
fragility
0.20
corrective polarity
clear
forced direction
lower s toward OFF branch
Chemistry feasibility (DIRECTION only [O]). small-molecule recrossing of the fold is geometrically harder (barrier 0.5555 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: lower s toward OFF 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).
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 pathological accumulation / over-activity from the PIK3CD GOF lesion does NOT relieve the disease branch in a PIK3CD model, the h-restore(clear) lever is refuted for this axis.
EXCLUDED: gain-of-function -- the lesion is not a destabilised healthy product to stiffen; the corrective move is to clear/oppose the toxic drive (h-restore)
Falsifier. If a folding-stabiliser/chaperone does NOT re-deepen the healthy well for a residual PIK3CD 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
✓ Agreement with established practice. The corrective direction derived here (lower s toward OFF branch) independently matches an agent already in clinical use for this disease: selective PI3K-delta inhibitor (leniolisib) suppressing the hyperactive PI3K-delta signalling of the PIK3CD gain-of-function lesion. The geometry recovered known medicine — this is a validation signal for the logic, not a new treatment claim by this kit.
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
selective PI3K-delta inhibitor (leniolisib) suppressing the hyperactive PI3K-delta signalling of the PIK3CD gain-of-function lesion
Walsh 2025 Cell 188:4861 (Scalable generation and functional classification of genetic variants in inborn errors of immunity to accelerate...); Luo 2018 Clin Immunol 197:60 (Identification of a novel de novo gain-of-function mutation of PIK3CD in a patient with activated phosphoinositide...)
decrease
approved
4
✓ in use
⚠ 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.
Mechanism. selective PI3K-delta inhibitor (leniolisib) suppressing the hyperactive PI3K-delta signalling of the PIK3CD gain-of-function lesion Direction: decrease the pathological accumulation / over-activity. Scope: agnostic (downstream).
✓ This is a rediscovery. Leniolisib is approved for activated PI3K-delta syndrome (APDS, PIK3CD gain-of-function); approved therapy recovered.
Safety (qualitative; no magnitude). established-use safety profile on record (qualitative; no magnitude)
Falsifier. If leniolisib (PI3K-delta inhibitor) [PIK3CD X-linked agammaglobulinemia-like] (a gene-specific decrease agent) clearing/opposing the accumulating load does NOT relieve the UP [F] disease branch in a PIK3CD model, the h-restore(clear) direction is refuted for leniolisib (PI3K-delta inhibitor) [PIK3CD X-linked agammaglobulinemia-like] here.
Source: Walsh 2025 Cell 188:4861 (Scalable generation and functional classification of genetic variants in inborn errors of immunity to accelerate...)
⚠ 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 PIK3CD; 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).