F618L

Category 5 — IDR ExclusionUncertain significanceTransmembrane · predictedSource card

Phenylalanine → Leucine at position 618 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type F618 — hydrogen bond to A616

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DynaMut2 mutant · F618L

Mutant L618 — hydrogen bond to A616 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost0 gained1 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	A616	—	Lost
Polar contact	A616	A616	Preserved
Hydrophobic	V620	—	Lost
Hydrophobic	M623	—	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

0.27kcal/mol

Stabilising — mild

AlphaMissense

0.390

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 5

Category 5 — IDR Exclusion

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

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

Population frequency (gnomAD v4)Ultra-rare · AF 0.000068%

cDNA changec.1852T>C

ClinVar accessionVCV003590716

Last evaluated2024/05/18 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — F618L Variant Card

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

Phenylalanine → Leucine at position 618. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.390, DynaMut2 ΔΔG +0.27 kcal/mol (stabilising).

Identity

Field	Value
Variant	F618L (p.Phenylalanine618Leucine)
DNA change	c.1852T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003590716
Amino acid change	Phenylalanine (F) → Leucine (L)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 618	44.22 — IDR (below 50 threshold)
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 618 projects into the ER lumen
IDR flag	YES — pLDDT below 50 (Cat 5)

UniProt features at this position:

(none catalogued)

Position 618 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	0.3899
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.27 (Stabilising)
Job ID	178094710361
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094710361

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2024/05/18 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	F618L is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

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

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 5 — IDR Exclusion

<strong>Category 5 — IDR Exclusion</strong><br/><br/>pLDDT 44.22 is below 50; DynaMut2 result not trustworthy. Route to wet-lab.

Why this card matters. Position sits in a low-confidence region. Computational stability estimates here are unreliable; this variant needs experimental characterization before any therapeutic strategy is set.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
F618L_molstar_viewer.html — interactive 3D viewer (auto-highlights position 618 with ball-and-stick + neighbors within 5Å)
F618L_variant_card.md — this card (source of truth)
F618L_variant_card.html — styled printable card
F618L_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)
F618L_wildtype_interactions.pse / F618L_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 F618L 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 F618L PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.