R177S

Category 3/4 — Most DruggableUncertain significanceCytoplasmic · predictedSource card

Arginine → Serine at position 177 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type R177 — ionic bond to E169

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DynaMut2 mutant · R177S

Mutant S177 — ionic bond to E169 lost (13 contacts lost)

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Bond changes · DynaMut2 interaction analysis

13 lost0 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	E169	—	Lost
Hydrogen bond	A134	—	Lost
Hydrogen bond	K135	—	Lost
Hydrogen bond	E173	E173	Preserved
Hydrogen bond	R174	R174	Preserved
Hydrogen bond	A180	—	Lost
Hydrogen bond	L181	L181	Preserved
Polar contact	A134	—	Lost
Polar contact	K135	—	Lost
Polar contact	E169	—	Lost
Polar contact	E173	E173	Preserved
Polar contact	R174	R174	Preserved
Polar contact	A175	A175	Preserved
Polar contact	A179	—	Lost
Polar contact	A180	A180	Preserved
Polar contact	L181	L181	Preserved
Van der Waals	L166	—	Lost
Van der Waals	E169	—	Lost
Van der Waals	A175	A175	Preserved
Van der Waals	A179	—	Lost
Van der Waals	L181	L181	Preserved
Hydrophobic	L181	—	Lost
Hydrophobic	V248	—	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

-1.44kcal/mol

Destabilising — moderate

AlphaMissense

0.994

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.000068%

cDNA changec.529C>A

ClinVar accessionVCV004763782

Last evaluated2025/07/13 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — R177S Variant Card

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

Arginine → Serine at position 177. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.994, DynaMut2 ΔΔG -1.44 kcal/mol (destabilising).

Identity

Field	Value
Variant	R177S (p.Arginine177Serine)
DNA change	c.529C>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV004763782
Amino acid change	Arginine (R) → Serine (S)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 177	90.81 — well-folded
Domain	N-terminal cytoplasmic (intrinsically disordered)
Position context	N-terminal cytoplasmic (intrinsically disordered)
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 177 sits in N-terminal cytoplasmic (intrinsically disordered). The wild-type residue is positively charged (arginine — guanidinium, strong H-bond donor); 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	0.9941
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.44 (Destabilising)
Job ID	178092087002
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092087002

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2025/07/13 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	R177S 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 3/4 — Most Druggable

<strong>Category 3/4 — Most Druggable</strong><br/><br/>|ΔΔG|=1.44 < 2 kcal/mol (fold intact) + AlphaMissense 0.994 confirms functional impact. Specific local contacts disrupted — priority for docking and pharmacological chaperone screening.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.44 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.994. 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
R177S_molstar_viewer.html — interactive 3D viewer (auto-highlights position 177 with ball-and-stick + neighbors within 5Å)
R177S_variant_card.md — this card (source of truth)
R177S_variant_card.html — styled printable card
R177S_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)
R177S_wildtype_interactions.pse / R177S_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 R177S 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 R177S PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.