Y351S

Category 2 — Moderately DestabilizingUncertain significanceTransmembrane · predictedSource card

Tyrosine → Serine at position 351 · Transmembrane helix 2 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type Y351 — hydrogen bond to I355

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DynaMut2 mutant · Y351S

Mutant S351 — hydrogen bond to I427 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost1 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L347	L347	Preserved
Hydrogen bond	—	F354	Gained
Hydrogen bond	I355	I355	Preserved
Hydrogen bond	I427	—	Lost
Polar contact	L347	L347	Preserved
Polar contact	V348	V348	Preserved
Polar contact	F354	F354	Preserved
Polar contact	I355	I355	Preserved
Polar contact	C426	—	Lost
Polar contact	P428	—	Lost
Van der Waals	I355	I355	Preserved
Hydrophobic	L347	—	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

-3.33kcal/mol

Destabilising — large

AlphaMissense

0.413

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 2

Category 2 — Moderately Destabilizing

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1052A>C

ClinVar accessionVCV002110305

Last evaluated2022/03/14 00:00

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Full Variant Card

WFS1 Wolframin — Y351S Variant Card

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

Tyrosine → Serine at position 351. Transmembrane helix 2. ClinVar Uncertain significance, AlphaMissense 0.413, DynaMut2 ΔΔG -3.33 kcal/mol (destabilising).

Identity

Field	Value
Variant	Y351S (p.Tyrosine351Serine)
DNA change	c.1052A>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002110305
Amino acid change	Tyrosine (Y) → Serine (S)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 351	91.88 — well-folded
Domain	Transmembrane helix 2
Position context	Inside Transmembrane helix 2 · position 351 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 351 sits in a transmembrane helix (Transmembrane helix 2). 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	0.4129
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-3.33 (Destabilising)
Job ID	178094701512
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094701512

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2022/03/14 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	Y351S 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 2 — Moderately Destabilizing

<strong>Category 2 — Moderately Destabilizing</strong><br/><br/>|ΔΔG|=3.33 in the 2–4 range. Pharmacological chaperone candidate.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
Y351S_molstar_viewer.html — interactive 3D viewer (auto-highlights position 351 with ball-and-stick + neighbors within 5Å)
Y351S_variant_card.md — this card (source of truth)
Y351S_variant_card.html — styled printable card
Y351S_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)
Y351S_wildtype_interactions.pse / Y351S_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 Y351S 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 Y351S PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.