V412D

Category 2 — Moderately DestabilizingUncertain significanceTransmembrane · predictedSource card

Valine → Aspartic acid at position 412 · Transmembrane helix 4 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type V412 — hydrogen bond to F408

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DynaMut2 mutant · V412D

Mutant D412 — hydrogen bond to V415 lost (7 contacts lost)

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Bond changes · DynaMut2 interaction analysis

7 lost1 gained11 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	M357	M357	Preserved
Hydrogen bond	F408	F408	Preserved
Hydrogen bond	L409	L409	Preserved
Hydrogen bond	V415	V415	Preserved
Hydrogen bond	I416	I416	Preserved
Hydrogen bond	—	M539	Gained
Polar contact	M357	—	Lost
Polar contact	F408	F408	Preserved
Polar contact	L409	L409	Preserved
Polar contact	F414	—	Lost
Polar contact	V415	V415	Preserved
Polar contact	I416	I416	Preserved
Van der Waals	F408	—	Lost
Van der Waals	F414	—	Lost
Van der Waals	I416	—	Lost
Hydrophobic	M357	M357	Preserved
Hydrophobic	F408	—	Lost
Hydrophobic	I416	—	Lost
Hydrophobic	M539	M539	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

-2.42kcal/mol

Destabilising — large

AlphaMissense

0.965

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 2

Category 2 — Moderately Destabilizing

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsInborn genetic diseases

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1235T>A

ClinVar accessionVCV001317197

Last evaluated2026/01/20 00:00

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

Full Variant Card

WFS1 Wolframin — V412D Variant Card

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

Valine → Aspartic acid at position 412. Transmembrane helix 4. ClinVar Uncertain significance, AlphaMissense 0.965, DynaMut2 ΔΔG -2.42 kcal/mol (destabilising).

Identity

Field	Value
Variant	V412D (p.Valine412Aspartic acid)
DNA change	c.1235T>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001317197
Amino acid change	Valine (V) → Aspartic acid (D)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 412	93.69 — well-folded
Domain	Transmembrane helix 4
Position context	Inside Transmembrane helix 4 · position 412 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 412 sits in a transmembrane helix (Transmembrane helix 4). 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 small hydrophobic (valine — branched); 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	0.9652
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-2.42 (Destabilising)
Job ID	178092098285
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092098285

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2026/01/20 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	V412D 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 2 — Moderately Destabilizing

<strong>Category 2 — Moderately Destabilizing</strong><br/><br/>|ΔΔG|=2.42 in the 2–4 range. Pharmacological chaperone candidate.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
V412D_molstar_viewer.html — interactive 3D viewer (auto-highlights position 412 with ball-and-stick + neighbors within 5Å)
V412D_variant_card.md — this card (source of truth)
V412D_variant_card.html — styled printable card
V412D_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)
V412D_wildtype_interactions.pse / V412D_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 V412D 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 V412D PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.