S662P

Category 3/4 — Most DruggableUncertain significanceLumenal · predictedσ-1 candidateSource card

Serine → Proline at position 662 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type S662 — hydrogen bond to R697

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DynaMut2 mutant · S662P

Mutant P662 — hydrogen bond to R697 lost (5 contacts lost)

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Bond changes · DynaMut2 interaction analysis

5 lost2 gained5 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	Y660	Y660	Preserved
Hydrogen bond	L664	—	Lost
Hydrogen bond	H696	H696	Preserved
Hydrogen bond	R697	—	Lost
Polar contact	Y660	Y660	Preserved
Polar contact	L664	—	Lost
Polar contact	H696	H696	Preserved
Polar contact	R697	R697	Preserved
Polar contact	V698	—	Lost
Van der Waals	—	Y660	Gained
Van der Waals	L664	—	Lost
Hydrophobic	—	H696	Gained

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

-0.14kcal/mol

Destabilising — mild

AlphaMissense

0.989

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

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

Population frequency (gnomAD v4)Ultra-rare · AF 0.0019%

cDNA changec.1984T>C

ClinVar accessionVCV000166600

Last evaluated2025/12/23 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — S662P Variant Card

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

Serine → Proline at position 662. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.989, DynaMut2 ΔΔG -0.14 kcal/mol (destabilising).

Identity

Field	Value
Variant	S662P (p.Serine662Proline)
DNA change	c.1984T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000166600
Amino acid change	Serine (S) → Proline (P)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 662	72.81 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 662 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 662 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 polar (serine — hydroxyl); the mutant is rigid/helix-breaking (proline — kinks backbone). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.9891
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.14 (Destabilising)
Job ID	178092088981
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092088981

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/12/23 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	S662P is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

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

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 3/4 — Most Druggable

<strong>Category 3/4 — Most Druggable</strong><br/><br/>|ΔΔG|=0.14 < 2 kcal/mol (fold intact) + AlphaMissense 0.989 confirms functional impact. Specific local contacts disrupted — priority for docking and pharmacological chaperone screening.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.14 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.989. 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
S662P_molstar_viewer.html — interactive 3D viewer (auto-highlights position 662 with ball-and-stick + neighbors within 5Å)
S662P_variant_card.md — this card (source of truth)
S662P_variant_card.html — styled printable card
S662P_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)
S662P_wildtype_interactions.pse / S662P_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 S662P 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 S662P PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.