D211N

Category 5 — IDR ExclusionPathogenic/Likely pathogenicCytoplasmic · predictedEditorial

Aspartate → Asparagine at position 211 · N-terminal cytoplasmic domain (87-313) · WFS1 (Wolframin)

Aspartate-to-asparagine substitution in a low-confidence region of the N-terminal cytoplasmic domain (pLDDT 44.56, below the IDR threshold) — the Atlas's structural framework cannot make confident claims here, and the schema correctly exits to wet-lab characterization.

Interactive 3D Structure

Wild-type reference

Wild-type D211 — hydrogen bond to N208

Fullscreen ↗

DynaMut2 mutant · D211N

Mutant N211 — energy-minimized; local contact network preserved

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

0 lost0 gained1 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	N208	N208	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

0.67kcal/mol

Stabilising — mild

AlphaMissense

0.093

LBen

AlphaFold pLDDT

model confidence

Schema

Cat 5

Category 5 — IDR Exclusion

Clinical Evidence

ClinVar classificationPathogenic/Likely pathogenic

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsWolfram syndrome 1; Wolfram-like syndrome; Cataract 41; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Inborn genetic diseases

InheritanceInheritance pattern documented as both autosomal dominant (deafness 6) and within Wolfram-spectrum disorders.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0018%

cDNA changec.631G>A

ClinVar accessionVCV000215378

Last evaluated2025/10/29 00:00

Observed at very low frequency in gnomAD.

Structural Context

D211 has only four neighbors within 5 Angstrom: Gly212 (2.43 Angstrom), His210 (2.45 Angstrom), Asn208 (4.57 Angstrom), and Glu209 (4.88 Angstrom). The minimal contact set and the low pLDDT are mutually reinforcing — both indicate that the local conformation is either intrinsically disordered or only weakly ordered in the AlphaFold ensemble. The structural inferences any computational pipeline would normally make at this resolution are not supported by the model.

The wild-type aspartate at 211 plausibly forms hydrogen bonds with H210 (an immediate neighbor whose imidazole could donate to the D211 carboxylate) and with E209 or N208 via secondary contacts. The D-to-N substitution removes the negative charge but preserves the hydrogen-bonding capacity; in fact, asparagine adds a hydrogen-bond donor (the amide NH2) where aspartate had only acceptors (the carboxylate oxygens). The net polar character is preserved but the electrostatic anchor is gone.

DynaMut2 reports DeltaDeltaG = +0.67 kcal/mol — stabilising and at the upper edge of the trustworthy bucket. AlphaMissense scores D211N at 0.093 (Likely Benign, well below the 0.564 threshold). Both computational metrics suggest the variant is structurally well-tolerated. The classification metadata explicitly flags this variant as not trustworthy for stability prediction because of the low pLDDT.

ClinVar nonetheless records D211N as Pathogenic/Likely pathogenic with multiple submitters across a broad phenotype spectrum (Cataract 41, AD hearing loss 6, type 2 diabetes, Wolfram syndrome 1, Wolfram-like syndrome). This is a third metric-discordant case in this batch — the structural and computational evidence argues against pathogenicity, while ClinVar curators have found clinical evidence for it. The reconciliation likely involves: (a) loss of an electrostatic anchor that the static AlphaFold model cannot evaluate because the region is dynamic, (b) ATP6V1A-binding interface disruption that affects function rather than fold, or (c) co-segregation with another variant in some families.

Amino-acid chemistry

Aspartate (negatively charged carboxylate side chain) to Asparagine (neutral amide side chain — same heavy-atom count and roughly the same volume, differing only in charge state and hydrogen-bonding profile) at position 211. The substitution is one of the most conservative possible chemistry-wise but removes the negative charge.

Position in the protein

Position 211 sits inside wolframin's N-terminal cytoplasmic domain (residues 87-313), within the UniProt-annotated ATP6V1A interaction region (residues 1-321). pLDDT 44.56 is below the IDR exclusion threshold (50) — the AlphaFold model is signaling that this region is likely disordered or has multiple conformations.

Druggability Assessment

Final classification: Category 5 — IDR Exclusion. The pLDDT (44.56) is below the structural confidence threshold; the schema correctly excludes D211N from the docking-and-structural-design pipeline and routes it to wet-lab characterization. The DynaMut2 metadata explicitly marks the stability prediction as not trustworthy for this position. This does not mean D211N is unimportant — the ClinVar phenotype breadth is substantial and the variant's recurrence across cataract, hearing loss, type 2 diabetes, and Wolfram-spectrum cases is clinically significant. It means that confident druggability assessment requires either an experimental structure of the local region, an NMR ensemble, or a functional assay (e.g., ATP6V1A-binding measurement) before therapeutic strategy can be designed. The Atlas's role here is to honestly identify the variant as one where structural-only inference is insufficient.

Why this matters

D211N is the canonical Category 5 case in this batch — a clinically important variant the Atlas's current framework cannot confidently characterize. The right scientific position is to acknowledge the limit. The Atlas's value to a clinical user is not undermined by saying this is where we need wet-lab data, it is enhanced. For the wolframin program, Category 5 variants like D211N are the experimental priority list. If the rare-disease research community can produce even modest functional data on D211N (an ATP6V1A binding assay, a cellular wolframin expression measurement, a cysteine modification profile), the Atlas can move D211N out of the exclusion bucket and into a defined category. Identifying which Category 5 variants are clinically common (D211N appears in multiple phenotype categories with multi-submitter ClinVar support) helps prioritize that experimental effort.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the D211N 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 D211N PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Region1–321 · Interaction with ATP6V1A