R146C

Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorial

Arginine → Cysteine at position 146 · N-terminal cytoplasmic domain (87-313) · WFS1 (Wolframin)

Arginine → Cysteine at position 146 in N-terminal cytoplasmic domain. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.19 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.38. R→C class.

Interactive 3D Structure

Wild-type reference

Wild-type R146 — hydrogen bond to A150

Fullscreen ↗

DynaMut2 mutant · R146C

Mutant C146 — hydrogen bond to S167 lost (2 contacts lost)

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

2 lost0 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	V142	V142	Preserved
Hydrogen bond	K143	K143	Preserved
Hydrogen bond	L149	L149	Preserved
Hydrogen bond	A150	A150	Preserved
Hydrogen bond	S167	—	Lost
Polar contact	V142	V142	Preserved
Polar contact	K143	K143	Preserved
Polar contact	L144	L144	Preserved
Polar contact	L149	L149	Preserved
Polar contact	A150	A150	Preserved
Polar contact	S167	—	Lost
Van der Waals	L144	L144	Preserved

Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.

Computational Predictions

DynaMut2 ΔΔG

-0.38kcal/mol

Destabilising — mild

AlphaMissense

0.195

LBen

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditionsWolfram syndrome 1

InheritanceWolfram syndrome 1.

Population frequency (gnomAD v4)Ultra-rare · AF 0.00021%

cDNA changec.436C>T

ClinVar accessionVCV000517251

Last evaluated2017/02/16 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 146 in cytoplasmic domain. Neighbors: ARG147 (2.4 Å — adjacent existing arginine), LEU145 (2.5 Å), LYS143 (3.8 Å). R146-R147 adjacent positives + K143 nearby — positively-charged surface patch.

R146C eliminates one of the cluster's positives + introduces thiol. AM 0.19 under-call; Wolfram 1 confirms.

Amino-acid chemistry

Arginine (R) → Cysteine (C) — charge loss + thiol introduction.

Position in the protein

N-terminal cytoplasmic domain · position 146 (pLDDT 92).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| 0.38. AlphaMissense 0.19 below threshold but Wolfram 1 confirms.

Mechanism: charge loss from R146-R147-K143 cluster. Therapeutic: site-directed at cytoplasmic recognition surface.

Why this matters

R146C continues R→C class (now 9+ variants).

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the R146C PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.

Download R146C PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Region1–321 · Interaction with ATP6V1A