# WFS1 Wolframin — E202G Variant Card **Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill** *Glutamate-to-glycine substitution in wolframin's N-terminal cytoplasmic ATP6V1A-interaction region — a low AlphaMissense score (0.283, Likely Benign) sits in tension with the ClinVar Pathogenic/Likely pathogenic classification, requiring careful interpretation.* --- ## Identity | Field | Value | |---|---| | **Variant** | E202G (p.Glutamate202Glycine) | | **DNA change** | c.605A>G | | **Gene · Protein** | WFS1 · Wolframin (890 aa) | | **UniProt** | O76024 · WFS1_HUMAN | | **ClinVar accession** | VCV000420050 | | **Amino acid change** | Glutamate (negatively charged carboxylate side chain) to Glycine (no side chain at all — backbone-only residue with unique torsional freedom) at position 202. The substitution removes both a charge and a side-chain heavy atom, replacing them with backbone flexibility. | --- ## Structural Context | Field | Value | |---|---| | **AlphaFold model** | AF-O76024-F1, v6 | | **pLDDT at residue 202** | **74.12** — well-folded | | **Domain** | N-terminal cytoplasmic domain (87-313) | | **Position context** | Position 202 sits inside wolframin's N-terminal cytoplasmic domain (residues 87-313), within the UniProt-annotated Region of interaction with ATP6V1A (residues 1-321). pLDDT 74.12 places E202 in a confidently modeled region. | | **IDR flag** | No — pLDDT above 50 threshold | **UniProt features at this position:** - Chain: 1-890 Wolframin - Region: 1-321 Interaction with ATP6V1A > E202 is held between Asn203 (2.46 Angstrom) and Leu201 (2.46 Angstrom) covalently, with through-space contacts to Ala198 (3.93 Angstrom), Glu199 (3.96 Angstrom), Val204 (4.36 Angstrom), and Leu200 (4.57 Angstrom). The local environment is mixed polar-aliphatic: two leucines, an alanine, a valine, an asparagine, and another glutamate (E199) within 4.5 Angstrom. The Glu199-Glu202 pair is interesting — two negatively charged carboxylates within 4 Angstrom likely participate in a coordinated electrostatic feature, either repelling each other to maintain extended conformation or both coordinating a divalent metal cation or a positively charged binding partner. The E202G substitution removes the side chain entirely. Glycine introduces backbone freedom where the wild-type maintained a side-chain-rigidified conformation. The Glu199-Glu202 coordinated electrostatic feature is destroyed — only Glu199 remains. If the wild-type pair coordinated a cation or formed part of an ATP6V1A-binding salt-bridge interface, that functionality is now lost. DynaMut2 reports DeltaDeltaG = -0.19 kcal/mol — essentially unchanged. AlphaMissense, however, scores E202G at 0.283 (Likely Benign by the AM classifier). This is a notable discordance with ClinVar's Pathogenic/Likely pathogenic classification. Three possible reconciliations: (a) the AM model under-weighs charge-removal mutations in surface-exposed regions; (b) ClinVar evidence for E202G derives from a small number of affected families and may include linkage to a separate causal variant; (c) the variant is genuinely a partial loss-of-function with subtle cellular consequences that AM does not detect. The structural signature — a Glu pair at the ATP6V1A-binding interface, broken by removal of one Glu — is functionally plausible. The Atlas should flag E202G as a discordant-metric variant requiring careful clinical follow-up rather than confident druggability assignment. --- ## Computational Predictions ### AlphaMissense | Field | Value | |---|---| | am_pathogenicity | **0.2830** | | am_class | **LBen** | | Interpretation | Likely benign (threshold 0.564) | ### DynaMut2 | Field | Value | |---|---| | ΔΔG (kcal/mol) | **-0.19 (Destabilising)** | | Job ID | 177991407826 | | Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991407826 | --- ## Clinical Evidence | Field | Value | |---|---| | Classification | **Pathogenic/Likely pathogenic** | | Review status | criteria provided, multiple submitters, no conflicts | | Last evaluated | 2024/06/04 00:00 | | Inheritance | Inheritance pattern not explicitly recorded. | | WFS1 variant landscape | E202G is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) | - Wolfram syndrome 1 - Optic atrophy --- ## 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** Final classification: Category 4 — Stable Fold, Function Disrupted, with metric-discordance caveat. The DeltaDeltaG magnitude (0.19 kcal/mol) is small; the pLDDT (74.12) is good; the AlphaMissense score (0.283) is unusually low for a ClinVar-pathogenic variant. The structural-chemistry case for a functional-site disruption (loss of the Glu199-Glu202 electrostatic feature on the ATP6V1A-binding surface) is suggestive but not conclusive. For druggability, the metric discordance argues for clinical follow-up before therapeutic investment. If the ClinVar evidence is solid, the lesion is on a binding surface and is small-molecule-accessible. If the AlphaMissense score is reading the biology correctly, the variant may not require dedicated therapeutic effort. The recommendation is to validate the clinical phenotype attribution before launching a chaperone screen. **Why this card matters.** E202G is the Atlas's first cleanly-discordant case in this batch — ClinVar Pathogenic but AlphaMissense Likely Benign. These discordances are exactly the variants the Atlas should surface for human review, not paper over. The schema does not force a confident druggability call when the underlying metrics disagree. The broader lesson is that the Atlas's value comes partly from honest flagging of cases where the available evidence is internally inconsistent. A real-world variant database will contain many such cases, and the right Atlas behavior is to report the discordance, frame the most plausible interpretation, and direct the clinical user to the specific data points that resolve the ambiguity. E202G is a teachable example for how the Atlas handles metric tension. --- ## Files in this folder - `AF-O76024-F1-model_v6.pdb` — AlphaFold structure - `E202G_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 202 with ball-and-stick + neighbors within 5Å) - `E202G_variant_card.md` — this card (source of truth) - `E202G_variant_card.html` — styled printable card - `E202G_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) - `E202G_wildtype_interactions.pse` / `E202G_mutant_interactions.pse` — PyMOL sessions --- *Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas* *Every assumption documented. Every score sourced.*