D118A

Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorial

Aspartate → Alanine at position 118 · N-terminal cytoplasmic domain (87-313) · WFS1 (Wolframin)

Aspartate → Alanine at position 118 in N-terminal cytoplasmic domain. ClinVar Conflicting including monogenic diabetes. AlphaMissense 0.35 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.14 kcal/mol (mild destabilising).

Interactive 3D Structure

Wild-type reference

Wild-type D118 — hydrogen bond to L121

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DynaMut2 mutant · D118A

Mutant A118 — hydrogen bond to L121 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost0 gained5 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L121	—	Lost
Hydrogen bond	N122	N122	Preserved
Polar contact	E120	E120	Preserved
Polar contact	L121	L121	Preserved
Polar contact	N122	N122	Preserved
Van der Waals	E120	—	Lost
Hydrophobic	L121	L121	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

-0.14kcal/mol

Destabilising — mild

AlphaMissense

0.352

Amb

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 conditionsMonogenic diabetes

InheritanceMonogenic diabetes.

Population frequency (gnomAD v4)Low frequency · AF 0.049%

cDNA changec.353A>C

ClinVar accessionVCV000178584

Last evaluated2026/01/21 00:00

Observed in the general population.

Structural Context

Position 118 sits in wolframin's N-terminal cytoplasmic domain. Neighbors: GLU119 (2.5 Å — adjacent existing glutamate), THR117 (2.5 Å), ASN122 (4.4 Å). The wild-type D118 + adjacent E119 form a charged surface patch in the cytoplasmic domain — likely a recognition surface for partner proteins.

Replacing D118 with alanine eliminates one of two negative charges from this patch. The local electrostatic surface is reduced; the partner-recognition geometry that depended on the D118-E119 double-negative signature is perturbed.

The |ΔΔG| of 0.14 is small — the fold absorbs the substitution. AlphaMissense's 0.35 is below threshold (AM under-call). Monogenic diabetes clinical evidence confirms pathogenicity through cytoplasmic partner-recognition disruption.

Amino-acid chemistry

Aspartate (D) → Alanine (A) — small negatively-charged carboxylate replaced by small methyl-bearing hydrophobic. Charge lost + side chain reduced.

Position in the protein

N-terminal cytoplasmic domain · position 118 (pLDDT 82).

Druggability Assessment

Category 4 — Stable Fold, Function Disrupted (AM under-call). |ΔΔG| = 0.14. AlphaMissense 0.35 below threshold but monogenic diabetes confirms pathogenicity.

Mechanism: charge loss from D118-E119 cytoplasmic surface patch. Therapeutic strategy: site-directed at the cytoplasmic recognition surface.

Why this matters

D118A is part of the charge-cluster-loss class in the N-terminal cytoplasmic domain (with similar patterns at E158K, E169K, E202G, E301K).

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the D118A 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 D118A PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Region1–321 · Interaction with ATP6V1A