E550V

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

Glutamic acid → Valine at position 550 · Transmembrane helix 8 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type E550 — ionic bond to K424

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DynaMut2 mutant · E550V

Mutant V550 — ionic bond to K424 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost1 gained5 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	K424	—	Lost
Hydrogen bond	K424	—	Lost
Hydrogen bond	I547	I547	Preserved
Polar contact	K424	—	Lost
Polar contact	I547	I547	Preserved
Polar contact	L548	L548	Preserved
Van der Waals	—	L548	Gained
Hydrophobic	F419	F419	Preserved
Hydrophobic	C429	C429	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

-0.08kcal/mol

Destabilising — mild

AlphaMissense

0.450

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 conditions—

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1649A>T

ClinVar accessionVCV001315759

Last evaluated2019/10/04 00:00

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

Full Variant Card

WFS1 Wolframin — E550V Variant Card

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

Glutamic acid → Valine at position 550. Transmembrane helix 8. ClinVar Uncertain significance, AlphaMissense 0.450, DynaMut2 ΔΔG -0.08 kcal/mol (destabilising).

Identity

Field	Value
Variant	E550V (p.Glutamic acid550Valine)
DNA change	c.1649A>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001315759
Amino acid change	Glutamic acid (E) → Valine (V)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 550	85.00 — well-folded
Domain	Transmembrane helix 8
Position context	Inside Transmembrane helix 8 · position 550 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 550 sits in a transmembrane helix (Transmembrane helix 8). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. The wild-type residue is negatively charged (glutamate — carboxylate); the mutant is small hydrophobic (valine — branched). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.4497
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.08 (Destabilising)
Job ID	178094707244
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094707244

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2019/10/04 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	E550V 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 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=0.08 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.08 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.450. 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
E550V_molstar_viewer.html — interactive 3D viewer (auto-highlights position 550 with ball-and-stick + neighbors within 5Å)
E550V_variant_card.md — this card (source of truth)
E550V_variant_card.html — styled printable card
E550V_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)
E550V_wildtype_interactions.pse / E550V_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 E550V 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 E550V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.