F417S

Category 2 — Moderately DestabilizingUncertain significanceTransmembrane · predictedSource card

Phenylalanine → Serine at position 417 · Transmembrane helix 4 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type F417 — hydrogen bond to F413

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DynaMut2 mutant · F417S

Mutant S417 — hydrogen bond to F413 lost (6 contacts lost)

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Bond changes · DynaMut2 interaction analysis

6 lost5 gained5 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	F413	F413	Preserved
Hydrogen bond	—	F414	Gained
Hydrogen bond	P420	P420	Preserved
Hydrogen bond	—	I421	Gained
Polar contact	F413	F413	Preserved
Polar contact	—	F414	Gained
Polar contact	V415	V415	Preserved
Polar contact	—	P420	Gained
Polar contact	I421	I421	Preserved
Aromatic / π	F413	—	Lost
Van der Waals	V415	—	Lost
Van der Waals	—	P420	Gained
Van der Waals	I421	—	Lost
Hydrophobic	F413	—	Lost
Hydrophobic	V875	—	Lost
Hydrophobic	A878	—	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

DynaMut2 ΔΔG

-2.01kcal/mol

Destabilising — large

AlphaMissense

0.657

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 2

Category 2 — Moderately Destabilizing

ΔΔG confidence: Reduced confidence · Transmembrane

transmembrane position; predictor benchmarked on soluble proteins

This variant sits in the transmembrane band. The stability value was computed with a predictor benchmarked on water-soluble proteins. Published benchmarks of ddG predictors on membrane proteins report correlation below 0.4. Treat the magnitude as unreliable and the sign as weak evidence only.

Do not rank this value against a variant from a different region on ΔΔG alone.

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.000068%

cDNA changec.1250T>C

ClinVar accessionVCV003675121

Last evaluated2024/07/19 00:00

Observed at very low frequency in gnomAD.

Classified for1★ unverified submission

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: 1★ single submitter. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.

Population frequency

Global (all ancestries)

AF 0.000068% · 1 / 1,461,880 alleles

Homozygotes

Every ancestry group with observed alleles falls below the reporting threshold (min 2 alleles, min 500 sampled) — too sparse to name a highest-frequency population.

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) · under-sampled	0.000090%	1 / 1,112,012	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 — F417S Variant Card

Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill

Phenylalanine → Serine at position 417. Transmembrane helix 4. ClinVar Uncertain significance, AlphaMissense 0.657, DynaMut2 ΔΔG -2.01 kcal/mol (destabilising).

Identity

Field	Value
Variant	F417S (p.Phenylalanine417Serine)
DNA change	c.1250T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003675121
Amino acid change	Phenylalanine (F) → Serine (S)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 417	87.75 — well-folded
Domain	Transmembrane helix 4
Position context	Inside Transmembrane helix 4 · position 417 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 417 sits in a transmembrane helix (Transmembrane helix 4). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. The wild-type residue is large aromatic hydrophobic (phenylalanine); 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	0.6572
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-2.01 (Destabilising)
Job ID	178092129019
Result URL	Job 178092129019 · 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

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, single submitter
Last evaluated	2024/07/19 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	F417S 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 2 — Moderately Destabilizing

<strong>Category 2 — Moderately Destabilizing</strong><br/><br/>|ΔΔG|=2.01 in the 2–4 range. Pharmacological chaperone candidate.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
F417S_molstar_viewer.html — interactive 3D viewer (auto-highlights position 417 with ball-and-stick + neighbors within 5Å)
F417S_variant_card.md — this card (source of truth)
F417S_variant_card.html — styled printable card
F417S_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)
F417S_wildtype_interactions.pse / F417S_mutant_interactions.pse — PyMOL sessions

Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas Every assumption documented. Every score sourced.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the F417S 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 F417S PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.