Y650C

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Tyrosine → Cysteine at position 650 · TM10 (632-652), helical transmembrane · WFS1 (Wolframin)

Tyrosine → Cysteine at position 650 inside TM10. ClinVar Conflicting including Cataract 41 + DFNA6. AlphaMissense 0.399 (below threshold), ΔΔG +0.31. Third Atlas variant at position 650 (with Y650H, Y650D).

Interactive 3D Structure

Wild-type reference

Wild-type Y650 — hydrogen bond to C647

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DynaMut2 mutant · Y650C

Mutant C650 — hydrogen bond to I338 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost1 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	I338	—	Lost
Hydrogen bond	F646	F646	Preserved
Hydrogen bond	C647	C647	Preserved
Hydrogen bond	R653	—	Lost
Hydrogen bond	S654	S654	Preserved
Polar contact	F646	F646	Preserved
Polar contact	C647	C647	Preserved
Polar contact	W648	W648	Preserved
Polar contact	Y652	—	Lost
Polar contact	R653	R653	Preserved
Polar contact	S654	S654	Preserved
Van der Waals	—	F646	Gained
Van der Waals	W648	—	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

0.31kcal/mol

Stabilising — mild

AlphaMissense

0.399

Amb

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditionsCataract 41; Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

InheritanceAD: Cataract + DFNA6.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0042%

cDNA changec.1949A>G

ClinVar accessionVCV001218633

Last evaluated2024/10/24 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 650 same neighbors as Y650H/Y650D: PHE649 (2.5 Å), VAL651 (2.5 Å), CYS647 (3.7 Å — C647 already in close contact!), PHE646 (3.7 Å). The C647 contact suggests a potential Y650C-C647 disulfide formation.

Y650C is the THIRD substitution at position 650. The new C650 could potentially form a disulfide with C647 (3.7 Å away) — possibly a beneficial or aberrant chemistry depending on the wild-type C647 state. Compare with Y650H (preserved aromatic) and Y650D (charge introduction).

AM 0.399 below threshold; multi-phenotype confirms.

Amino-acid chemistry

Tyrosine (Y) → Cysteine (C) — aromatic phenol replaced by thiol. Loss of aromatic + introduction of disulfide-capable thiol.

Position in the protein

TM10 (residues 632–652) · position 650 (pLDDT 69 borderline).

Druggability Assessment

Category 4 — Stable Fold, Function Disrupted (AM under-call). ΔΔG +0.31. AlphaMissense 0.399 below threshold but multi-phenotype confirms pathogenicity.

Mechanism: aromatic loss + potential aberrant disulfide with C647. Therapeutic: same Y650 microregion as Y650H/Y650D.

Why this matters

Y650C completes the Y650 three-substitution series (Y650H, Y650D, Y650C) — position 650 is a multi-substitution hotspot in TM10.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the Y650C 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 Y650C PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane632–652 · Helical