F649L

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

Phenylalanine → Leucine at position 649 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type F649 — hydrogen bond to L645

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DynaMut2 mutant · F649L

Mutant L649 — polar contact contact to R653 lost

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Bond changes · DynaMut2 interaction analysis

0 lost1 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L645	L645	Preserved
Hydrogen bond	F646	F646	Preserved
Hydrogen bond	Y652	Y652	Preserved
Hydrogen bond	R653	R653	Preserved
Polar contact	L645	L645	Preserved
Polar contact	F646	F646	Preserved
Polar contact	C647	C647	Preserved
Polar contact	R653	R653	Preserved
Van der Waals	—	C647	Gained
Hydrophobic	R653	R653	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

0.27kcal/mol

Stabilising — mild

AlphaMissense

0.511

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 conditionsWolfram syndrome 1

Population frequency (gnomAD v4)Ultra-rare · AF 0.00034%

cDNA changec.1947C>G

ClinVar accessionVCV002430204

Last evaluated1/01/01 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — F649L Variant Card

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

Phenylalanine → Leucine at position 649. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.511, DynaMut2 ΔΔG +0.27 kcal/mol (stabilising).

Identity

Field	Value
Variant	F649L (p.Phenylalanine649Leucine)
DNA change	c.1947C>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002430204
Amino acid change	Phenylalanine (F) → Leucine (L)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 649	70.44 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 649 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 649 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 large aromatic hydrophobic (phenylalanine); the mutant is medium hydrophobic (leucine — branched). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.5112
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.27 (Stabilising)
Job ID	178094706074
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094706074

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	1/01/01 00:00
Inheritance	Autosomal recessive Wolfram syndrome 1 phenotype documented.
WFS1 variant landscape	F649L is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Wolfram syndrome 1

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|=0.27 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.27 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.511. 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
F649L_molstar_viewer.html — interactive 3D viewer (auto-highlights position 649 with ball-and-stick + neighbors within 5Å)
F649L_variant_card.md — this card (source of truth)
F649L_variant_card.html — styled printable card
F649L_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)
F649L_wildtype_interactions.pse / F649L_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 F649L 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 F649L PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.