A844T

Category 4 — Stable Fold, Function DisruptedUncertain significanceLumenal · predictedσ-1 candidateSource card

Alanine → Threonine at position 844 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type A844 — hydrogen bond to S826

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DynaMut2 mutant · A844T

Mutant T844 — hydrogen bond to V861 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost1 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	F825	—	Lost
Hydrogen bond	S826	S826	Preserved
Hydrogen bond	V861	—	Lost
Polar contact	F825	F825	Preserved
Polar contact	S826	S826	Preserved
Polar contact	L842	L842	Preserved
Polar contact	V861	V861	Preserved
Carbonyl	F825	—	Lost
Van der Waals	F825	—	Lost
Van der Waals	S826	S826	Preserved
Van der Waals	—	K862	Gained
Hydrophobic	K862	K862	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

-0.91kcal/mol

Destabilising — mild

AlphaMissense

0.480

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 conditionsAutosomal dominant nonsyndromic hearing loss 6

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.2530G>A

ClinVar accessionVCV003392512

Last evaluated1/01/01 00:00

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

Full Variant Card

WFS1 Wolframin — A844T Variant Card

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

Alanine → Threonine at position 844. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.480, DynaMut2 ΔΔG -0.91 kcal/mol (destabilising).

Identity

Field	Value
Variant	A844T (p.Alanine844Threonine)
DNA change	c.2530G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003392512
Amino acid change	Alanine (A) → Threonine (T)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 844	87.62 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 844 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 844 sits in the C-terminal lumenal domain (residues 653–869), wolframin's largest soluble region. This domain projects into the ER lumen and is implicated in calcium handling, ER stress sensing, and protein–protein interactions with ATF6 and Na+/K+ ATPase β1. The wild-type residue is small/hydrophobic (alanine — methyl sidechain); the mutant is small polar (threonine — hydroxyl). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.4796
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.91 (Destabilising)
Job ID	178094717198
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094717198

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	1/01/01 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	A844T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Autosomal dominant nonsyndromic hearing loss 6

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|=0.91 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.91 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.480. 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
A844T_molstar_viewer.html — interactive 3D viewer (auto-highlights position 844 with ball-and-stick + neighbors within 5Å)
A844T_variant_card.md — this card (source of truth)
A844T_variant_card.html — styled printable card
A844T_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)
A844T_wildtype_interactions.pse / A844T_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 A844T 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 A844T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.