H323L

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

Histidine → Leucine at position 323 · Transmembrane helix 1 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type H323 — hydrogen bond to P320

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DynaMut2 mutant · H323L

Mutant L323 — energy-minimized; local contact network preserved

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Bond changes · DynaMut2 interaction analysis

0 lost0 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	P320	P320	Preserved
Hydrogen bond	A326	A326	Preserved
Hydrogen bond	L327	L327	Preserved
Polar contact	P320	P320	Preserved
Polar contact	A326	A326	Preserved
Polar contact	L327	L327	Preserved
Hydrophobic	P320	P320	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

1.70kcal/mol

Stabilising — moderate

AlphaMissense

0.424

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain risk allele

Review statuscriteria provided, single submitter

Associated conditionsWolfram syndrome 1

Population frequency (gnomAD v4)Ultra-rare · AF 0.00025%

cDNA changec.968A>T

ClinVar accessionVCV001810353

Last evaluated1/01/01 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — H323L Variant Card

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

Histidine → Leucine at position 323. Transmembrane helix 1. ClinVar Uncertain risk allele, AlphaMissense 0.424, DynaMut2 ΔΔG +1.70 kcal/mol (stabilising).

Identity

Field	Value
Variant	H323L (p.Histidine323Leucine)
DNA change	c.968A>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001810353
Amino acid change	Histidine (H) → Leucine (L)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 323	76.94 — well-folded
Domain	Transmembrane helix 1
Position context	Inside Transmembrane helix 1 · position 323 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 323 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 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	0.4242
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	1.7 (Stabilising)
Job ID	178094699642
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094699642

Clinical Evidence

Field	Value
Classification	Uncertain risk allele
Review status	criteria provided, single submitter
Last evaluated	1/01/01 00:00
Inheritance	Autosomal recessive Wolfram syndrome 1 phenotype documented.
WFS1 variant landscape	H323L is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Wolfram syndrome 1

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|=1.70 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.70 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.424. 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
H323L_molstar_viewer.html — interactive 3D viewer (auto-highlights position 323 with ball-and-stick + neighbors within 5Å)
H323L_variant_card.md — this card (source of truth)
H323L_variant_card.html — styled printable card
H323L_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)
H323L_wildtype_interactions.pse / H323L_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 H323L 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 H323L PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.