R138G

Category 3/4 — Most DruggableUncertain significanceCytoplasmic · predictedSource card

Arginine → Glycine at position 138 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type R138 — hydrogen bond to V142

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DynaMut2 mutant · R138G

Mutant G138 — hydrogen bond to A141 lost (9 contacts lost)

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Bond changes · DynaMut2 interaction analysis

9 lost0 gained5 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	P100	—	Lost
Hydrogen bond	A133	A133	Preserved
Hydrogen bond	A141	—	Lost
Hydrogen bond	V142	V142	Preserved
Polar contact	P100	—	Lost
Polar contact	T104	—	Lost
Polar contact	A133	A133	Preserved
Polar contact	E140	—	Lost
Polar contact	A141	—	Lost
Polar contact	V142	V142	Preserved
Van der Waals	K101	—	Lost
Van der Waals	A133	A133	Preserved
Hydrophobic	A133	—	Lost
Hydrophobic	A141	—	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

-1.06kcal/mol

Destabilising — moderate

AlphaMissense

0.609

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 conditionsInborn genetic diseases

Population frequency (gnomAD v4)Ultra-rare · AF 0.000070%

cDNA changec.412C>G

ClinVar accessionVCV004201395

Last evaluated2025/08/31 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — R138G Variant Card

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

Arginine → Glycine at position 138. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.609, DynaMut2 ΔΔG -1.06 kcal/mol (destabilising).

Identity

Field	Value
Variant	R138G (p.Arginine138Glycine)
DNA change	c.412C>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV004201395
Amino acid change	Arginine (R) → Glycine (G)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 138	89.06 — 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 138 sits in N-terminal cytoplasmic (intrinsically disordered). The wild-type residue is positively charged (arginine — guanidinium, strong H-bond donor); the mutant is small/flexible (glycine — backbone flexibility, no sidechain). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.6085
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.06 (Destabilising)
Job ID	178092131018
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092131018

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2025/08/31 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	R138G is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Inborn genetic diseases

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|=1.06 < 2 kcal/mol (fold intact) + AlphaMissense 0.609 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|=1.06 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.609. 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
R138G_molstar_viewer.html — interactive 3D viewer (auto-highlights position 138 with ball-and-stick + neighbors within 5Å)
R138G_variant_card.md — this card (source of truth)
R138G_variant_card.html — styled printable card
R138G_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)
R138G_wildtype_interactions.pse / R138G_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 R138G 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 R138G PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.