R517C

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Arginine → Cysteine at position 517 · Connecting loop · WFS1 (Wolframin)

Arginine → Cysteine at position 517 in connecting loop. ClinVar Conflicting including Wolfram-like + Cataract 41. AlphaMissense 0.16 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.89. Same loop region as M518I, M518K.

Interactive 3D Structure

Wild-type reference

Wild-type R517 — hydrogen bond to L521

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DynaMut2 mutant · R517C

Mutant C517 — hydrogen bond contact to Y513 lost

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Bond changes · DynaMut2 interaction analysis

1 lost1 gained12 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	Y513	Y513	Preserved
Hydrogen bond	L514	L514	Preserved
Hydrogen bond	Q520	Q520	Preserved
Hydrogen bond	L521	L521	Preserved
Polar contact	Y513	Y513	Preserved
Polar contact	L514	L514	Preserved
Polar contact	F515	F515	Preserved
Polar contact	Q520	Q520	Preserved
Polar contact	L521	L521	Preserved
Van der Waals	—	Y513	Gained
Van der Waals	F515	F515	Preserved
Van der Waals	A519	A519	Preserved
Hydrophobic	Y454	Y454	Preserved
Hydrophobic	Y513	—	Lost

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

-0.89kcal/mol

Destabilising — mild

AlphaMissense

0.157

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-like syndrome; Cataract 41; Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

InheritanceMulti-phenotype.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0040%

cDNA changec.1549C>T

ClinVar accessionVCV001396272

Last evaluated2025/04/15 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 517 in connecting loop, immediately upstream of M518 (M518I, M518K). Neighbors: MET518 (2.5 Å — M518 multi-variant position!), PHE516 (2.5 Å), LEU514 (3.7 Å).

R517C removes positive charge from the local environment. The M518 multi-variant position (M518I, M518K) and now R517C converge on the 514-521 loop region. AM 0.16 under-call; multi-phenotype confirms.

Amino-acid chemistry

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

Position in the protein

Connecting loop · position 517 (pLDDT 88).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| 0.89. AlphaMissense 0.16 below threshold but THREE phenotypes confirm pathogenicity.

Mechanism: charge loss + thiol in M518 multi-variant cluster. Therapeutic: same 514-521 loop as M518I/K.

Why this matters

R517C + M518I + M518K — three variants in adjacent positions converge.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the R517C 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 R517C PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin