ACTG2 · Q247P

① sequence context · ACTG2

−4     Q247     +4
Conservation · Q247
9/9 ConSurf · invariant
phyloP100way7.87/ max ≈ 10
phastCons100way1.000/ max = 1
VarSome · chr2:73,914,805 · hg38

② residue chemistry

N Cα C=O H NH donor × no NH Cβ Cγ C=O NH₂ flexible Cβ Cγ Cδ pyrrolidine φ free · PPII φ locked Glutamine Q247 · wild-type
The flexible glutamine side chain and free backbone dihedral allow Q247 to adopt multiple conformations — essential for actin subdomain 3 dynamics during filament assembly.
Ramachandran plot φ (°) ψ (°) −180 0 +180 +180 0 −180 Q247 P247 35% allowed
35% of total backbone conformational space is accessible for Gln — the loop can explore many conformations, required for actin subdomain 3 to adapt during filament formation. Lovell et al. 2003 Proteins 50:437

③ structural parameters

④ actin polymerization

going deeper

Why is Q247P a pathogenic mutation? ▾
1. Evolutionary conservation. Q247 is invariant across all 6 human actin isoforms and in vertebrates from fish to mammals (ConSurf 9/9). phastCons100way = 1.000 (maximum possible) and phyloP100way = 7.87 (strong purifying selection, max ≈ 10).

2. Structural disruption. The substitution simultaneously abolishes the backbone NH H-bond, locks the backbone dihedral (Ramachandran freedom: 35% → 8%), and buries 45 Ų of surface.

3. Absence in healthy populations. Q247P is absent from gnomAD (>125,000 exomes, >76,000 genomes).
What is the structural consequence for γ-2 actin? ▾
Q247 sits in the subdomain 3 loop of actin, mediating inter-subunit contacts in the filament. Three direct structural consequences:

Loss of H-bond. The backbone NH of Q247 stabilizes the loop. Proline's tertiary N cannot donate this bond, destabilizing the loop conformation.

Backbone rigidification. The pyrrolidine ring locks φ ≈ −60°, reducing conformational freedom from 35% to 8% of Ramachandran space.

Reduced surface exposure. SASA drops 40% (−45.4 Ų), burying surface previously available for actin–actin contacts.