H313Y

H313 is held between Met312 (2.44 Angstrom) and Trp314 (2.47 Angstrom). Through-space contacts include Ser316 (3.63 Angstrom), Ala310 (3.92 Angstrom), Arg309 (4.00 Angstrom), Gly311 (4.50 Angstrom), and Leu315 (4.54 Angstrom). Trp314 is structurally striking — a tryptophan at the cytoplasmic edge of TM1 is the classical interfacial-anchor residue, embedding the membrane-helix start at the bilayer interface. The Met312-His313-Trp314 sequence places H313 at a hinge point: a sulfur-bearing residue, an imidazole, and an interfacial aromatic, all within a single short stretch.

Replacing H313 with tyrosine introduces a second large aromatic immediately next to the interfacial Trp314. Two large aromatics in sequence at a membrane interface can either pi-stack productively (potentially stabilizing the transition into TM1) or compete for the interfacial position (destabilizing the Trp314 anchor). DynaMut2 reports DeltaDeltaG = +1.20 kcal/mol — stabilising, larger magnitude than most variants in this batch. The energy function is reading a productive Tyr313-Trp314 aromatic interaction.

AlphaMissense, in striking contrast, scores H313Y at 0.167 — Likely Benign, well below the 0.564 pathogenicity threshold. The discordance with ClinVar Pathogenic/Likely pathogenic is even sharper than for E202G. Possible reconciliations: (a) the variant is genuinely benign and ClinVar's pathogenicity classification was driven by limited evidence that may warrant reclassification; (b) the Atlas's metrics are underweighing a real functional consequence at the cytoplasmic-TM1 boundary; (c) ClinVar evidence reflects compound-heterozygous cases where H313Y is not the causal allele.

The stabilising DeltaDeltaG, the low AM score, and the structurally plausible Tyr-Trp aromatic interaction together suggest the variant may indeed be functionally tolerated. The Atlas should flag H313Y for ClinVar evidence review rather than confidently assign druggability category.