| Mutation | Type | Residual transport activity | Structural location | Population prevalence / recurrence | Functional/pathogenic note |
|---|---|---:|---|---|---|
| **F188del** | In-frame deletion | Defective; markedly reduced activity | Likely TM4 / pore region | ~30% of reported HHH patients; enriched in French-Canadian cases (pqac-00000015, pqac-00000021) | One of the two most common HHH alleles; affects a residue lining the internal translocation pore, consistent with impaired substrate translocation (pqac-00000015) |
| **R179\*** (also reported as **R179X**) | Nonsense | Predicted null | Contact-point II / pore-facing region, near matrix gate | ~15% of reported HHH patients; recurrent in Japanese and Middle Eastern/Palestinian families (pqac-00000015, pqac-00000020, pqac-00000021, pqac-00000022) | Truncates ORC1; residue 179 is a key determinant of substrate recognition in wild-type ORC1, so loss is expected to abolish transport (pqac-00000004, pqac-00000015) |
| **M37R** | Missense | ~0% (virtually incapable of transport) | TM1 / matrix salt-bridge network region (H1) (pqac-00000017, pqac-00000018) | Novel/reported in HHH families; no major founder prevalence stated (pqac-00000017) | Disrupts salt-bridge networks critical for carrier gating and strongly impairs transport of ornithine, arginine, lysine, and citrulline (pqac-00000017, pqac-00000018) |
| **L71Q** | Missense | Reduced; within reported mutant range of ~4–19% of wild type | TM2 / H2 helix package (pqac-00000017, pqac-00000018) | Reported in HHH families; no major founder prevalence stated (pqac-00000017) | Hydrophilic substitution perturbs H2 helix packing and carrier structural integrity (pqac-00000017) |
| **A15V** | Missense | Nearly abolished / dramatically inhibited | N-terminal region / early TM1 vicinity (pqac-00000016) | Identified in a Turkish patient (pqac-00000016, pqac-00000021) | Functional assay showed near-complete loss of ornithine transport, supporting pathogenicity (pqac-00000016) |
| **G27E** | Missense | Defective; exact % not stated | TM1 / pore-proximal region | Recurrent in Japanese patients; also reported in Palestinian families (pqac-00000021, pqac-00000022) | Associated with decreased ornithine transport activity in liver mitochondria/ORC1 deficiency (pqac-00000021, pqac-00000022) |
| **G216S** | Missense | Reduced; within reported mutant range of ~4–19% of wild type | Likely TM5 / pore-facing region (pqac-00000017, pqac-00000018) | Reported in HHH families (pqac-00000017, pqac-00000020) | Alters carrier structure/function and contributes to markedly reduced transport (pqac-00000017, pqac-00000018) |
| **T272I** | Missense | Reduced; within reported mutant range of ~4–19% of wild type | TM6 region (pqac-00000017) | Reported in HHH families (pqac-00000017, pqac-00000020) | Causes steric interference with crucial intramolecular interactions required for catalytic function (pqac-00000017) |
| **L283F** | Missense | Reduced; within reported mutant range of ~4–19% of wild type | TM6 region / late C-terminal helix (pqac-00000017) | Reported in HHH families (pqac-00000017) | Bulky substitution likely perturbs helix packing and transport pathway geometry (pqac-00000017) |
| **E180K** | Missense | Pathogenic; exact residual % not stated | Contact-point II substrate-binding site near residue R179 (pqac-00000004, pqac-00000013, pqac-00000025) | Reported missense HHH allele (pqac-00000013) | E180 is a key substrate-binding residue in wild-type ORC1; substitution is expected to disrupt ligand recognition and translocation (pqac-00000004, pqac-00000025) |
| **F188D** | Missense | Pathogenic; exact residual % not stated | Around residue 188 in pore/TM4 region (pqac-00000013) | Reported missense HHH allele (pqac-00000013) | Missense change near the recurrent F188 hotspot; associated with HHH syndrome and impaired urea-cycle transport (pqac-00000013) |
| **P126R** | Missense | Defective; exact % not stated | Likely TM3 / central cavity region (pqac-00000021) | Reported in affected families (pqac-00000021) | Likely disrupts conserved carrier helix geometry important for alternating-access transport (pqac-00000021, pqac-00000023) |
| **R275X** | Nonsense | Predicted null | TM6 / contact-point III vicinity; R275 is mechanistically important in wild type (pqac-00000025, pqac-00000026) | Reported in affected families (pqac-00000021) | Premature stop removes C-terminal region; wild-type Arg275 contributes to substrate-triggered conformational change (pqac-00000025, pqac-00000026) |
| **T32R** | Missense | Defective; exact % not stated | TM1 / matrix-gate neighborhood (pqac-00000021, pqac-00000023) | Reported in affected families (pqac-00000021) | Likely perturbs local charge environment near matrix-side gating residues (pqac-00000021, pqac-00000023) |
| **p.K245X** | Nonsense | Predicted null | C-terminal half / likely TM5-TM6 region (pqac-00000017, pqac-00000018) | Identified among 13 mutations in HHH families (pqac-00000018, pqac-00000020) | Premature truncation expected to abolish functional carrier assembly/transport (pqac-00000017, pqac-00000018) |
| **p.S175fsX192** | Frameshift | Predicted null | Mid-protein / around TM4 entry (pqac-00000018) | Reported in HHH families (pqac-00000018) | Frameshift with premature termination; expected severe loss of ORC1 function (pqac-00000018) |
| **c.552-555delTTTC (p.Phe185SerfsTer8)** | Frameshift deletion | Predicted null | Around residue 185 / pore hotspot region (pqac-00000022) | Novel homozygous variant in 9 Palestinian patients (pqac-00000022) | Expected nonsense-mediated decay or severely truncated protein; expands the HHH molecular spectrum (pqac-00000022) |
| **c.446delG (p.Ser149ThrfsTer45)** | Frameshift deletion | Predicted null | Mid-protein / central carrier region (pqac-00000022) | Recurrent homozygous variant in 4 Palestinian patients (pqac-00000022) | Frameshift expected to abrogate transporter function; associated with marked clinical heterogeneity despite shared genotype (pqac-00000022) |
| **Overall missense class** | Missense | Typically ~4–19% of wild-type transport, except severe alleles such as M37R (~0%) and A15V (near-abolished) (pqac-00000018, pqac-00000019, pqac-00000016) | Frequently in transmembrane helices H1–H6 and residues protruding into the internal pore (pqac-00000017, pqac-00000023) | No clear genotype-phenotype correlation overall (pqac-00000015, pqac-00000019) | Many pathogenic residues cluster in the translocation pore or gating networks, interfering with substrate binding, helix movement, or conformational switching (pqac-00000015, pqac-00000017, pqac-00000026) |


*Table: This table summarizes representative disease-causing SLC25A15 variants reported in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, including mutation class, functional impact, structural context, and recurrence. It is useful for connecting genotype to transporter mechanism and clinical interpretation.*