C505S

Category 4 — Stable Fold, Function DisruptedUncertain significanceTransmembrane · predictedSource card

Cysteine → Serine at position 505 · Transmembrane helix 7 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type C505 — hydrogen bond to V509

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DynaMut2 mutant · C505S

Mutant S505 — hydrogen bond to F886 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost0 gained11 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	S502	S502	Preserved
Hydrogen bond	Y508	Y508	Preserved
Hydrogen bond	V509	V509	Preserved
Hydrogen bond	F886	F886	Preserved
Polar contact	N500	N500	Preserved
Polar contact	S502	S502	Preserved
Polar contact	V503	V503	Preserved
Polar contact	L507	—	Lost
Polar contact	Y508	Y508	Preserved
Polar contact	V509	V509	Preserved
Van der Waals	S502	S502	Preserved
Van der Waals	L507	L507	Preserved
Van der Waals	F886	—	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

-1.71kcal/mol

Destabilising — moderate

AlphaMissense

0.366

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.0027%

cDNA changec.1514G>C

ClinVar accessionVCV001013977

Last evaluated2024/07/30 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — C505S Variant Card

Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill

Cysteine → Serine at position 505. Transmembrane helix 7. ClinVar Uncertain significance, AlphaMissense 0.366, DynaMut2 ΔΔG -1.71 kcal/mol (destabilising).

Identity

Field	Value
Variant	C505S (p.Cysteine505Serine)
DNA change	c.1514G>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001013977
Amino acid change	Cysteine (C) → Serine (S)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 505	82.44 — well-folded
Domain	Transmembrane helix 7
Position context	Inside Transmembrane helix 7 · position 505 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 505 sits in a transmembrane helix (Transmembrane helix 7). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. The wild-type residue is thiol (cysteine — disulfide-capable, free -SH); the mutant is small polar (serine — hydroxyl). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.3662
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.71 (Destabilising)
Job ID	178094712322
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094712322

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2024/07/30 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	C505S is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

(no conditions catalogued)

Research Path Decision Tree

ΔΔG < 2  + binding site affected   →  CATEGORY 3 — docking experiments
ΔΔG 2–4                            →  CATEGORY 2 — pharmacological chaperones
ΔΔG > 4                            →  CATEGORY 1 — gene therapy
pLDDT < 50                         →  CATEGORY 5 — IDR, experimental only
Stable fold + functional site hit  →  CATEGORY 4 — site-specific docking

Final Schema Categorization

Category 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=1.71 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.71 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.366. Protein still folds, but a specific local site is broken. Pharmacological chaperones and small-molecule binders are the rational therapeutic vector.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
C505S_molstar_viewer.html — interactive 3D viewer (auto-highlights position 505 with ball-and-stick + neighbors within 5Å)
C505S_variant_card.md — this card (source of truth)
C505S_variant_card.html — styled printable card
C505S_dynamut2_summary.html — clean offline DynaMut2 result card
dynamut2_result.json — structured result data
dynamut2_result_page.html — local snapshot of the Biosig result page (asset URLs absolutized)
C505S_wildtype_interactions.pse / C505S_mutant_interactions.pse — PyMOL sessions

Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas Every assumption documented. Every score sourced.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the C505S 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 C505S PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.