Autosomal dominant hypocalcaemia type 1 (CASR gain-of-function) OMIM 601198
In Autosomal dominant hypocalcaemia type 1 (CASR, OMIM 601198), the master switch sits on the ↓ DOWN branch ([F] forced below); the healthy state is the OFF well. The forced corrective direction is to lower s toward OFF branch (polarity: supply). 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 0.4422, γ 1.3299, spinodal 0.5903). 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 Autosomal dominant hypocalcaemia type 1 is an R19 double-well emerged from the real proximal-promoter DNA of CASR. Its geometry is fixed by measured stiffness γ (never fitted); the numbers below are read directly off that cusp.
emergent axis
↓ DOWN [F]
healthy branch
OFF
lesion
GOF
γ (stiffness)
1.3299
barrier
0.4422
spinodal
0.5903
s_on / s_off
1.1532 / -1.1532
fragility
0.73
corrective polarity
supply
forced direction
lower s toward OFF branch
Chemistry feasibility (DIRECTION only [O]). small-molecule recrossing of the fold is geometrically plausible (barrier 0.4422 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. supply / restore the positive drive (replace-or-agonise the missing competence)
Applies to. allele-agnostic (downstream/environmental tilt)
favoured when the switch is fragile -- a small drive shift recrosses the fold
Falsifier. If supplying/agonising calcium (raising the switch drive) does NOT move the DOWN [F] switch toward the healthy branch in a CASR-deficient model, the h-restore(supply) 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 CASR 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: active vitamin D (calcitriol) + calcium. 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
active vitamin D (calcitriol) + calcium
Lienhardt 2001 (cautious calcitriol/Ca in ADH)
increase
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. An investigational calcilytic (negative allosteric modulator of the calcium-sensing receptor) that relieves the activating CASR variant, allowing parathyroid-hormone secretion and renal calcium handling to rise toward normal. Direction on the disease axis: increase -- supply calcium competence by counteracting the gain-of-function receptor. Engaged node: CASR. Allele scope: gain-of-function-directed. Gene-specific to CASR; encoded as an increase lever, it MIRRORS the e6l cinacalcet entry: the two CASR diseases require opposite signs, so the join surfaces the calcilytic(increase) only on the activating-receptor node (autosomal dominant hypocalcemia type 1) and the calcimimetic(decrease) only on the loss-of-function node (neonatal severe hyperparathyroidism). INVESTIGATIONAL direction-only hypothesis (no efficacy/approval/availability claim); status per training knowledge to Jan 2026 -- confirm current development.
Prior-art. Direction-only hypothesis: the geometry derives an increase (raise calcium competence) for the activating-CASR node; the investigational calcilytic encaleret relieves the gain-of-function receptor, raising PTH/calcium, a matched increase. Mirrors the loss-of-function NSHPT node (cinacalcet, decrease); the sign filter isolates calcilytic(increase)->ADH1 from calcimimetic(decrease)->NSHPT. Investigational; confirm current status. No efficacy/availability claim.
Safety (qualitative; no magnitude). investigational; calcium-raising mechanism carries hypercalcaemia/hypercalciuria considerations (qualitative; no magnitude); confirm current development status
Falsifier. If encaleret (a gene-specific supply/increase agent) does NOT move the DOWN [F] switch toward the healthy branch in a CASR-deficient model, the h-restore(supply) direction is refuted for encaleret here.
Source: Encaleret (calcilytic) investigational programme in activating-CASR autosomal dominant hypocalcemia type 1
⚠ 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 CASR; 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).