S626F

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

Serine → Phenylalanine at position 626 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type S626 — hydrogen bond to G622

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DynaMut2 mutant · S626F

Mutant F626 — hydrogen bond contact to M623 lost

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Bond changes · DynaMut2 interaction analysis

0 lost0 gained12 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	G622	G622	Preserved
Hydrogen bond	M623	M623	Preserved
Hydrogen bond	R629	R629	Preserved
Polar contact	G622	G622	Preserved
Polar contact	M623	M623	Preserved
Polar contact	V624	V624	Preserved
Polar contact	T628	T628	Preserved
Polar contact	R629	R629	Preserved
Polar contact	M632	M632	Preserved
Van der Waals	V624	V624	Preserved
Van der Waals	T628	T628	Preserved
Van der Waals	M632	M632	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

-0.66kcal/mol

Destabilising — mild

AlphaMissense

0.365

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 conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.00043%

cDNA changec.1877C>T

ClinVar accessionVCV002438603

Last evaluated2023/01/09 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — S626F Variant Card

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

Serine → Phenylalanine at position 626. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.365, DynaMut2 ΔΔG -0.66 kcal/mol (destabilising).

Identity

Field	Value
Variant	S626F (p.Serine626Phenylalanine)
DNA change	c.1877C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002438603
Amino acid change	Serine (S) → Phenylalanine (F)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 626	51.03 — confident
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 626 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 626 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 large aromatic hydrophobic (phenylalanine). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.3651
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.66 (Destabilising)
Job ID	178094718718
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094718718

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2023/01/09 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	S626F 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|=0.66 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.66 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.365. 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
S626F_molstar_viewer.html — interactive 3D viewer (auto-highlights position 626 with ball-and-stick + neighbors within 5Å)
S626F_variant_card.md — this card (source of truth)
S626F_variant_card.html — styled printable card
S626F_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)
S626F_wildtype_interactions.pse / S626F_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 S626F 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 S626F PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.