PhenoFold

Short-limbed short stature with characteristic facial features (most common form of dwarfism)

• System Skeletal
• Inheritance autosomal dominant
• Region Gly380Arg in the transmembrane domain (residue 380)

Almost all achondroplasia is caused by a single recurrent substitution, Gly380Arg, in the transmembrane segment of fibroblast growth factor receptor 3. The change is generally understood to stabilise receptor dimers and produce constitutive (ligand-independent) signalling that suppresses growth-plate chondrocyte proliferation — a gain-of-function acting on receptor activation, not a loss of the receptor's fold.

Thick airway mucus, chronic lung infection, and pancreatic insufficiency

• System Respiratory
• Inheritance autosomal recessive
• Region Phe508del in nucleotide-binding domain 1 (NBD1) (residue 508)

The most common CF allele deletes a single phenylalanine (Phe508) from the first nucleotide-binding domain of the CFTR chloride channel. The residue sits at an NBD1 surface that contacts the membrane-spanning domains, and its loss is generally described as destabilising domain folding and assembly so that most protein is degraded before reaching the cell surface — a folding/trafficking defect rather than a change to the isolated NBD1 fold.

Progressive childhood-onset muscle weakness and wasting

• System Muscular
• Inheritance X-linked recessive
• Region Whole protein — most alleles are frameshifting deletions abolishing dystrophin

Duchenne muscular dystrophy usually results from out-of-frame deletions in the very large dystrophin gene that abolish production of the dystrophin protein, which normally links the muscle-cell cytoskeleton to the membrane. Because the common mechanism is loss of the whole protein rather than a single substitution, no single key residue is marked. Dystrophin is a long rod of spectrin-like repeats; its predicted model is low-confidence in many regions — interpret pLDDT before drawing conclusions about any part of the fold.

Very high LDL cholesterol from birth; premature coronary artery disease

• System Cardiovascular
• Inheritance autosomal dominant
• Region Ligand-binding and EGF-precursor domains (many variants across the receptor)

Familial hypercholesterolaemia is most often caused by variants in the LDL receptor, which clears LDL cholesterol from the blood. Hundreds of variants are known across the receptor's cysteine-rich ligand-binding and EGF-precursor domains; they are generally described as impairing folding, ligand binding, or trafficking so that fewer functional receptors reach the cell surface. No single residue dominates, so this entry marks no single key residue.

Progressive chorea, cognitive decline, and psychiatric change in mid-adult life

• System Nervous system
• Inheritance autosomal dominant
• Region N-terminal polyglutamine (polyQ) tract (expansion beyond ~36 CAG repeats)

Huntington disease is caused by expansion of a CAG-repeat that encodes a polyglutamine tract near the N-terminus of the huntingtin protein. Beyond roughly 36 repeats the expanded tract is generally understood to promote misfolding and aggregation of N-terminal fragments; huntingtin is very large and largely flexible, so this is a toxic gain-of-function of an expanded low-complexity region rather than disruption of a well-defined globular fold. The predicted model is low-confidence across much of the chain — read pLDDT before over-interpreting any region.

Tall stature, long limbs, lens dislocation, and aortic root dilatation

• System Connective tissue
• Inheritance autosomal dominant
• Region Calcium-binding EGF-like domains (many cysteine-affecting variants)

Marfan syndrome is caused by variants in fibrillin-1, a large extracellular matrix protein built from many tandem calcium-binding EGF-like domains. Many pathogenic variants alter conserved cysteines that form the disulfide bonds holding each small domain together; these are generally understood to misfold individual domains and disrupt microfibril assembly. No single residue dominates across patients, so this entry marks no single key residue. The predicted model of this long, repetitive, largely extracellular protein is low-confidence in many regions.

Elevated blood phenylalanine; untreated, causes intellectual disability (managed by low-Phe diet)

• System Metabolic
• Inheritance autosomal recessive
• Region Catalytic and regulatory domains (many disease alleles; most reduce enzyme stability/activity)

PKU results from reduced activity of phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine. Hundreds of different variants are known across the enzyme; many are generally described as destabilising the folded protein or its assembly so that functional enzyme is lost. Because no single residue dominates, this entry marks no single key residue — the mechanism is broadly loss of a stable, active enzyme.

Sickle-shaped red blood cells; chronic haemolytic anaemia and vaso-occlusive crises

• System Blood
• Inheritance autosomal recessive
• Region β6 (Glu→Val; residue 7 in UniProt numbering, which includes the initiator Met) (residue 7)

The classic β-globin substitution Glu6Val (position 6 in the mature chain; residue 7 in UniProt canonical numbering, which counts the initiator methionine) places a hydrophobic valine on the molecule's surface. This surface patch lets deoxygenated haemoglobin S polymerise into fibres, which is generally understood to deform the red cell — the folded monomer is little changed, so the effect is on assembly rather than on the single-chain fold.

Progressive neurodegeneration in infancy with a cherry-red macular spot

• System Nervous system
• Inheritance autosomal recessive
• Region α-subunit of β-hexosaminidase A (many alleles reduce enzyme activity/stability)

Tay-Sachs disease is caused by deficiency of the α-subunit of β-hexosaminidase A, so the GM2 ganglioside it normally degrades accumulates in neurons. Multiple alleles reduce enzyme activity or stability by different means; because no single residue dominates across patients, this entry marks no single key residue. The mechanism is broadly loss of a stable, active enzyme.