G656S
Category 5 — IDR ExclusionUncertain significanceLumenal · predictedσ-1 candidateSource cardInteractive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | R653 | R653 | Preserved |
| Hydrogen bond | K658 | K658 | Preserved |
| Polar contact | R653 | R653 | Preserved |
| Polar contact | S654 | S654 | Preserved |
| Polar contact | K658 | K658 | Preserved |
| Van der Waals | — | S654 | Gained |
| Van der Waals | K658 | — | Lost |
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 48.88 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 Uncertain significance, but does not state what it is classified for. ClinVar records no condition for this variant. A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
- 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 Remaining individuals: AF 0.0064% (4 of 62,478 alleles), 2.2x the global figure. The global AF describes the general population, not the at-risk group.
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. |
|---|---|---|---|---|
| Remaining individuals | 0.0064% | 4 / 62,478 | 0 | ~1 in 7810 |
| African / African American | 0.0053% | 4 / 74,926 | 0 | ~1 in 9370 |
| Admixed American | 0.0033% | 2 / 60,000 | 0 | ~1 in 15000 |
| European (non-Finnish) | 0.0029% | 34 / 1,180,040 | 0 | ~1 in 17350 |
| Finnish · under-sampled | 0.0016% | 1 / 63,538 | 0 | — |
| South Asian · under-sampled | 0.0011% | 1 / 91,086 | 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.
Full Variant Card
WFS1 Wolframin — G656S Variant Card
Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill
Glycine → Serine at position 656. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.511, DynaMut2 ΔΔG -0.06 kcal/mol (destabilising).
Identity
| Field | Value |
|---|---|
| Variant | G656S (p.Glycine656Serine) |
| DNA change | c.1966G>A |
| Gene · Protein | WFS1 · Wolframin (890 aa) |
| UniProt | O76024 · WFS1_HUMAN |
| ClinVar accession | VCV001014101 |
| Amino acid change | Glycine (G) → Serine (S) |
Structural Context
| Field | Value |
|---|---|
| AlphaFold model | AF-O76024-F1, v6 |
| pLDDT at residue 656 | 48.88 — IDR (below 50 threshold) |
| Domain | C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) |
| Position context | C-terminal lumenal domain · position 656 projects into the ER lumen |
| IDR flag | YES — pLDDT below 50 (Cat 5) |
UniProt features at this position:
(none catalogued)
Position 656 sits in the C-terminal lumenal domain (residues 653–869), wolframin's largest soluble region. This domain projects into the ER lumen and is implicated in calcium handling, ER stress sensing, and protein–protein interactions with ATF6 and Na+/K+ ATPase β1. The wild-type residue is small/flexible (glycine — backbone flexibility, no sidechain); the mutant is small polar (serine — hydroxyl). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.
Computational Predictions
AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | 0.5107 |
| am_class | ambiguous |
| Interpretation | Likely benign (threshold 0.564) |
DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | -0.06 (Destabilising) |
| Job ID | 178094713787 |
| Result URL | Job 178094713787 · retrieved 2026-06-08 — result self-hosted by RareResearch.AI (Biosig no longer serves this page) |
Clinical Evidence
Inheritance and scope
Uncertain significance — phenotype scope not stated in ClinVar
ClinVar classifies this variant as Uncertain significance, but does not state what it is classified for. ClinVar records no condition for this variant. A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
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.
| Field | Value |
|---|---|
| Classification | Uncertain significance |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2025/04/22 00:00 |
| Inheritance | Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations. |
| WFS1 variant landscape | G656S is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |
(no conditions catalogued)
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 5 — IDR Exclusion
<strong>Category 5 — IDR Exclusion</strong><br/><br/>pLDDT 48.88 is below 50; DynaMut2 result not trustworthy. Route to wet-lab.
Why this card matters. Position sits in a low-confidence region. Computational stability estimates here are unreliable; this variant needs experimental characterization before any therapeutic strategy is set.
Files in this folder
AF-O76024-F1-model_v6.pdb— AlphaFold structureG656S_molstar_viewer.html— interactive 3D viewer (auto-highlights position 656 with ball-and-stick + neighbors within 5Å)G656S_variant_card.md— this card (source of truth)G656S_variant_card.html— styled printable cardG656S_dynamut2_summary.html— clean offline DynaMut2 result carddynamut2_result.json— structured result datadynamut2_result_page.html— local snapshot of the Biosig result page (asset URLs absolutized)G656S_wildtype_interactions.pse/G656S_mutant_interactions.pse— PyMOL sessions
Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas Every assumption documented. Every score sourced.
Feed this card to Wolfram Intelligence
Download the G656S 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.