H294D

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

Histidine → Aspartic acid at position 294 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type H294 — hydrogen bond to Y291

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DynaMut2 mutant · H294D

Mutant D294 — polar contact to I296 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost0 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	Y291	Y291	Preserved
Hydrogen bond	M297	M297	Preserved
Hydrogen bond	E298	E298	Preserved
Polar contact	Y291	Y291	Preserved
Polar contact	P292	P292	Preserved
Polar contact	I296	—	Lost
Polar contact	M297	M297	Preserved
Polar contact	E298	E298	Preserved
Van der Waals	P292	P292	Preserved
Van der Waals	I296	—	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

0.13kcal/mol

Stabilising — mild

AlphaMissense

0.432

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsWolfram-like syndrome; Cataract 41; Type 2 diabetes mellitus; Autosomal dominant nonsyndromic hearing loss 6; Wolfram syndrome 1

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.880C>G

ClinVar accessionVCV002735327

Last evaluated2024/03/22 00:00

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Full Variant Card

WFS1 Wolframin — H294D Variant Card

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

Histidine → Aspartic acid at position 294. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.432, DynaMut2 ΔΔG +0.13 kcal/mol (stabilising).

Identity

Field	Value
Variant	H294D (p.Histidine294Aspartic acid)
DNA change	c.880C>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002735327
Amino acid change	Histidine (H) → Aspartic acid (D)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 294	62.28 — confident
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 294 sits in N-terminal cytoplasmic (intrinsically disordered). The wild-type residue is titratable basic (histidine — imidazole); the mutant is negatively charged (aspartate — carboxylate). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.4319
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.13 (Stabilising)
Job ID	178094711977
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094711977

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2024/03/22 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	H294D is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Wolfram-like syndrome
Cataract 41
Type 2 diabetes mellitus
Autosomal dominant nonsyndromic hearing loss 6
Wolfram syndrome 1

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|=0.13 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.13 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.432. 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
H294D_molstar_viewer.html — interactive 3D viewer (auto-highlights position 294 with ball-and-stick + neighbors within 5Å)
H294D_variant_card.md — this card (source of truth)
H294D_variant_card.html — styled printable card
H294D_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)
H294D_wildtype_interactions.pse / H294D_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 H294D 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 H294D PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.