H313P

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

Histidine → Proline at position 313 · Transmembrane helix 1 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type H313 — hydrogen bond to R309

Fullscreen ↗

DynaMut2 mutant · H313P

Mutant P313 — hydrogen bond contact to R309 lost

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

1 lost1 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	R309	R309	Preserved
Hydrogen bond	S316	S316	Preserved
Hydrogen bond	T317	T317	Preserved
Polar contact	R309	R309	Preserved
Polar contact	A310	—	Lost
Polar contact	S316	S316	Preserved
Polar contact	T317	T317	Preserved
Van der Waals	—	S316	Gained
Van der Waals	T317	T317	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

0.90kcal/mol

Stabilising — mild

AlphaMissense

0.545

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 conditions—

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

cDNA changec.938A>C

ClinVar accessionVCV001707064

Last evaluated2022/04/01 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — H313P Variant Card

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

Histidine → Proline at position 313. Transmembrane helix 1. ClinVar Uncertain significance, AlphaMissense 0.545, DynaMut2 ΔΔG +0.90 kcal/mol (stabilising).

Identity

Field	Value
Variant	H313P (p.Histidine313Proline)
DNA change	c.938A>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001707064
Amino acid change	Histidine (H) → Proline (P)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 313	57.41 — confident
Domain	Transmembrane helix 1
Position context	Inside Transmembrane helix 1 · position 313 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 313 sits in a transmembrane helix (Transmembrane helix 1). 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 titratable basic (histidine — imidazole); the mutant is rigid/helix-breaking (proline — kinks backbone). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.5451
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.9 (Stabilising)
Job ID	178094733914
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094733914

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2022/04/01 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	H313P 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 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=0.90 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.90 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.545. 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
H313P_molstar_viewer.html — interactive 3D viewer (auto-highlights position 313 with ball-and-stick + neighbors within 5Å)
H313P_variant_card.md — this card (source of truth)
H313P_variant_card.html — styled printable card
H313P_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)
H313P_wildtype_interactions.pse / H313P_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 H313P 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 H313P PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.