K811M

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

Lysine → Methionine at position 811 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type K811 — hydrogen bond to S808

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DynaMut2 mutant · K811M

Mutant M811 — polar contact to L814 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost0 gained12 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	S808	S808	Preserved
Hydrogen bond	L815	L815	Preserved
Polar contact	S808	S808	Preserved
Polar contact	E809	E809	Preserved
Polar contact	V813	V813	Preserved
Polar contact	L814	—	Lost
Polar contact	L815	L815	Preserved
Van der Waals	S808	S808	Preserved
Van der Waals	E809	E809	Preserved
Van der Waals	V813	—	Lost
Van der Waals	L815	L815	Preserved
Hydrophobic	Y773	Y773	Preserved
Hydrophobic	F775	F775	Preserved
Hydrophobic	L815	L815	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

-0.24kcal/mol

Destabilising — mild

AlphaMissense

0.508

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

Population frequency (gnomAD v4)Ultra-rare · AF 0.00031%

cDNA changec.2432A>T

ClinVar accessionVCV003590744

Last evaluated2025/05/15 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — K811M Variant Card

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

Lysine → Methionine at position 811. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.508, DynaMut2 ΔΔG -0.24 kcal/mol (destabilising).

Identity

Field	Value
Variant	K811M (p.Lysine811Methionine)
DNA change	c.2432A>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003590744
Amino acid change	Lysine (K) → Methionine (M)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 811	86.25 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 811 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 811 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 positively charged (lysine — primary amine); the mutant is hydrophobic sulfur (methionine). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.5084
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.24 (Destabilising)
Job ID	178094730105
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094730105

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/05/15 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	K811M is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

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

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|=0.24 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.24 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.508. 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
K811M_molstar_viewer.html — interactive 3D viewer (auto-highlights position 811 with ball-and-stick + neighbors within 5Å)
K811M_variant_card.md — this card (source of truth)
K811M_variant_card.html — styled printable card
K811M_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)
K811M_wildtype_interactions.pse / K811M_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 K811M 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 K811M PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.