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

Structural Context

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

DynaMut2

Clinical Evidence

Inheritance and scope

Uncertain significance — for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296); WFS1-related diabetes (autosomal dominant)

ClinVar classifies this variant as Uncertain significance for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296); WFS1-related diabetes (autosomal dominant). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.

This rests on a single submitter (1★). Treat the conditions above as submitted, not as documented phenotypes. Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient. Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.

• 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.