Y513S

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

Tyrosine → Serine at position 513 · Transmembrane helix 7 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type Y513 — hydrogen bond to R517

Fullscreen ↗

DynaMut2 mutant · Y513S

Mutant S513 — hydrogen bond to R517 lost (4 contacts lost)

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

4 lost0 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	V509	V509	Preserved
Hydrogen bond	Y510	Y510	Preserved
Hydrogen bond	F516	F516	Preserved
Hydrogen bond	R517	R517	Preserved
Polar contact	V509	V509	Preserved
Polar contact	Y510	Y510	Preserved
Polar contact	L511	L511	Preserved
Polar contact	F515	—	Lost
Polar contact	F516	F516	Preserved
Polar contact	R517	R517	Preserved
Van der Waals	L511	L511	Preserved
Van der Waals	F515	—	Lost
Hydrophobic	Y510	—	Lost
Hydrophobic	R517	—	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

-1.81kcal/mol

Destabilising — moderate

AlphaMissense

0.465

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 conditionsWFS1-Related Spectrum Disorders; Cataract 41; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram syndrome 1; Wolfram-like syndrome

Population frequency (gnomAD v4)Ultra-rare · AF 0.0056%

cDNA changec.1538A>C

ClinVar accessionVCV000215412

Last evaluated2025/08/27 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — Y513S Variant Card

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

Tyrosine → Serine at position 513. Transmembrane helix 7. ClinVar Uncertain significance, AlphaMissense 0.465, DynaMut2 ΔΔG -1.81 kcal/mol (destabilising).

Identity

Field	Value
Variant	Y513S (p.Tyrosine513Serine)
DNA change	c.1538A>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000215412
Amino acid change	Tyrosine (Y) → Serine (S)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 513	89.88 — well-folded
Domain	Transmembrane helix 7
Position context	Inside Transmembrane helix 7 · position 513 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 513 sits in a transmembrane helix (Transmembrane helix 7). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. The wild-type residue is aromatic with hydroxyl (tyrosine — H-bond donor/acceptor); the mutant is small polar (serine — hydroxyl). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.4652
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.81 (Destabilising)
Job ID	178094703388
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094703388

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/08/27 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	Y513S is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

WFS1-Related Spectrum Disorders
Cataract 41
Autosomal dominant nonsyndromic hearing loss 6
Type 2 diabetes mellitus
Wolfram syndrome 1
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 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=1.81 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.81 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.465. 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
Y513S_molstar_viewer.html — interactive 3D viewer (auto-highlights position 513 with ball-and-stick + neighbors within 5Å)
Y513S_variant_card.md — this card (source of truth)
Y513S_variant_card.html — styled printable card
Y513S_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)
Y513S_wildtype_interactions.pse / Y513S_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 Y513S 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 Y513S PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.