A575G

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Alanine → Glycine at position 575 · TM8 (563-583), helical transmembrane · WFS1 (Wolframin)

Alanine → Glycine at position 575 inside TM8. ClinVar Conflicting with broad spectrum — Wolfram-like, Cataract 41, Wolfram. AlphaMissense 0.14 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.41.

Interactive 3D Structure

Wild-type reference

Wild-type A575 — hydrogen bond to P571

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DynaMut2 mutant · A575G

Mutant G575 — hydrogen bond to I572 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost2 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	P571	P571	Preserved
Hydrogen bond	I572	—	Lost
Hydrogen bond	A578	A578	Preserved
Hydrogen bond	L579	L579	Preserved
Polar contact	P571	P571	Preserved
Polar contact	—	I572	Gained
Polar contact	A578	A578	Preserved
Polar contact	L579	L579	Preserved
Van der Waals	P571	—	Lost
Van der Waals	—	L573	Gained

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

-0.41kcal/mol

Destabilising — mild

AlphaMissense

0.140

LBen

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditionsWolfram-like syndrome; Cataract 41; Wolfram syndrome 1

InheritanceMulti-phenotype.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0050%

cDNA changec.1724C>G

ClinVar accessionVCV000440419

Last evaluated2025/11/05 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 575 in TM8. Neighbors: VAL574 (2.5 Å), GLY576 (2.5 Å — G576S partner!), PRO571 (3.7 Å).

A575G removes side chain creating cavity. Adjacent to G576S (Atlas card). Three Atlas variants in TM8 (A569V, A575G, G576S). AM 0.14 under-call; multi-phenotype confirms.

Amino-acid chemistry

Alanine (A) → Glycine (G) — small methyl-bearing replaced by smallest amino acid. Side chain removed.

Position in the protein

TM8 (residues 563–583) · position 575 (pLDDT 81).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| 0.41. AlphaMissense 0.14 below threshold but three phenotypes confirm.

Mechanism: cavity creation in TM8. Therapeutic: TM8 multi-variant cluster.

Why this matters

A575G extends TM8 cluster — A569V + A575G + G576S now converge.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the A575G 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 A575G PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane563–583 · Helical