P607A

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

Proline → Alanine at position 607 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type P607 — hydrogen bond to R611

Fullscreen ↗

DynaMut2 mutant · P607A

Mutant A607 — hydrogen bond to C604 lost (4 contacts lost)

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

4 lost0 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	C604	—	Lost
Hydrogen bond	L610	L610	Preserved
Hydrogen bond	R611	R611	Preserved
Polar contact	V603	—	Lost
Polar contact	C604	—	Lost
Polar contact	L610	L610	Preserved
Polar contact	R611	R611	Preserved
Van der Waals	R611	—	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

-0.22kcal/mol

Destabilising — mild

AlphaMissense

0.418

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

Population frequency (gnomAD v4)Ultra-rare · AF 0.0017%

cDNA changec.1819C>G

ClinVar accessionVCV001523954

Last evaluated2024/03/20 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — P607A Variant Card

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

Proline → Alanine at position 607. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.418, DynaMut2 ΔΔG -0.22 kcal/mol (destabilising).

Identity

Field	Value
Variant	P607A (p.Proline607Alanine)
DNA change	c.1819C>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001523954
Amino acid change	Proline (P) → Alanine (A)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 607	65.88 — confident
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 607 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 607 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 rigid/helix-breaking (proline — kinks backbone); the mutant is small/hydrophobic (alanine — methyl sidechain). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.4180
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.22 (Destabilising)
Job ID	178094727366
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094727366

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2024/03/20 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	P607A is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

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

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|=0.22 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.22 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.418. 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
P607A_molstar_viewer.html — interactive 3D viewer (auto-highlights position 607 with ball-and-stick + neighbors within 5Å)
P607A_variant_card.md — this card (source of truth)
P607A_variant_card.html — styled printable card
P607A_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)
P607A_wildtype_interactions.pse / P607A_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 P607A 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 P607A PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.