R177H

Category 3/4 — Most DruggableUncertain significanceCytoplasmic · predictedSource card

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

Interactive 3D Structure

Wild-type reference

Wild-type R177 — ionic bond to E169

Fullscreen ↗

DynaMut2 mutant · R177H

Mutant H177 — ionic bond to E169 lost (10 contacts lost)

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

10 lost5 gained13 preserved

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

-1.11kcal/mol

Destabilising — moderate

AlphaMissense

0.854

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 0.00034%

cDNA changec.530G>A

ClinVar accessionVCV001320924

Last evaluated2019/05/21 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — R177H Variant Card

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

Arginine → Histidine at position 177. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.854, DynaMut2 ΔΔG -1.11 kcal/mol (destabilising).

Identity

Field	Value
Variant	R177H (p.Arginine177Histidine)
DNA change	c.530G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001320924
Amino acid change	Arginine (R) → Histidine (H)

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 titratable basic (histidine — imidazole). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.8544
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.11 (Destabilising)
Job ID	178092112591
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092112591

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2019/05/21 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	R177H 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|=1.11 < 2 kcal/mol (fold intact) + AlphaMissense 0.854 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|=1.11 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.854. 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
R177H_molstar_viewer.html — interactive 3D viewer (auto-highlights position 177 with ball-and-stick + neighbors within 5Å)
R177H_variant_card.md — this card (source of truth)
R177H_variant_card.html — styled printable card
R177H_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)
R177H_wildtype_interactions.pse / R177H_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 R177H 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 R177H PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.