D211N
Category 5 — IDR ExclusionPathogenic/Likely pathogenicCytoplasmic · predictedEditorialAspartate-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
Bond changes · DynaMut2 interaction analysis
| 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
- pLDDT 44.56 below 70
The underlying AlphaFold model has pLDDT below 70 at this position, so the structure the stability calculation was run on is itself uncertain.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Pathogenic/Likely pathogenic for Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 2★ multiple submitters, no conflicts. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.0023% (27 of 1,179,988 alleles), in line with the global figure.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| European (non-Finnish) | 0.0023% | 27 / 1,179,988 | 0 | ~1 in 21850 |
| Remaining individuals · under-sampled | 0.0016% | 1 / 62,454 | 0 | — |
| African / African American · under-sampled | 0.0013% | 1 / 74,922 | 0 | — |
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
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.
Druggability Assessment
Why this matters
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.