| Gene symbol | Functional pathway / class | Evidence-supported notes | Inheritance mode if explicitly stated | Key quantitative facts supported in current evidence | Key sources with URLs and years |
|---|---|---|---|---|---|
| **BMPR2** | BMP/TGF-β signaling; type II BMP receptor | Most prevalent HPAH gene; included in 12-gene “definitive evidence” list; HPAH most often caused by heterozygous BMPR2 variants; pathogenic variants drive small-vessel narrowing via increased proliferation and reduced apoptosis; BMPR2 carriers tend to present younger, with worse hemodynamics and higher risk of death/lung transplant (pqac-00000017, pqac-00000016, pqac-00000019, pqac-00000015) | **AD with incomplete penetrance** (pqac-00000016) | >80% familial/heritable cases; ~17% idiopathic PAH; penetrance ~30% overall, 42% in heterozygous women, 14% in heterozygous men; >800 independent pathogenic variants reported (pqac-00000015, pqac-00000016, pqac-00000017, pqac-00000018) | Li & Quigley 2024, https://doi.org/10.1042/BST20231547; Eichstaedt et al. 2023, https://doi.org/10.1183/13993003.01471-2022; Kovacs et al. 2024, https://doi.org/10.1183/13993003.01324-2024 |
| **ACVRL1** | BMP/TGF-β signaling; type I receptor (ALK1) | Included in definitive-evidence PAH gene list; HHT-associated PAH gene; PAH may be first sign of later HHT in some carriers (pqac-00000019, pqac-00000016) | **AD** for HHT context explicitly stated (pqac-00000016) | ACVRL1-associated PAH median onset reported at **20 years** (pqac-00000016) | Eichstaedt et al. 2023, https://doi.org/10.1183/13993003.01471-2022; Kovacs et al. 2024, https://doi.org/10.1183/13993003.01324-2024 |
| **ENG** | BMP/TGF-β signaling; co-receptor endoglin | Included in definitive-evidence PAH gene list; HHT-associated PAH gene (pqac-00000019, pqac-00000016) | **AD** for HHT context explicitly stated (pqac-00000016) | No gene-specific HPAH frequency quantified in current evidence (pqac-00000016, pqac-00000019) | Eichstaedt et al. 2023, https://doi.org/10.1183/13993003.01471-2022; Kovacs et al. 2024, https://doi.org/10.1183/13993003.01324-2024 |
| **SMAD4** | BMP/TGF-β signaling mediator | Reported as HHT/PAH-predisposing gene in consensus genetics statement (pqac-00000016) | Not explicitly stated for isolated PAH in current evidence | No quantitative HPAH estimate retrieved in current evidence (pqac-00000016) | Eichstaedt et al. 2023, https://doi.org/10.1183/13993003.01471-2022 |
| **SMAD9** | BMP/TGF-β signaling; SMAD effector | Included in definitive-evidence PAH gene list; recognized BMP-pathway PAH gene (pqac-00000019, pqac-00000015) | Not explicitly stated in current evidence | No quantitative frequency retrieved in current evidence (pqac-00000019, pqac-00000015) | Kovacs et al. 2024, https://doi.org/10.1183/13993003.01324-2024; Li & Quigley 2024, https://doi.org/10.1042/BST20231547 |
| **GDF2** | BMP/TGF-β signaling; ligand BMP9 | Included in definitive-evidence list; validated PAH gene in BMP pathway; GDF2 variant carriers in Taiwanese cohort were younger and had lower circulating GDF2; possible modifier role proposed (pqac-00000019, pqac-00000018, pqac-00000006) | Not explicitly stated in current evidence | European-descent PAH: **0.8–1.2%**; Asian PAH: **6.7%** in one cited review; plasma GDF2 **135.6 ± 36.2 pg/mL vs 267.8 ± 185.8 pg/mL**, *p*=0.002 in variant vs non-BMPR2/non-GDF2 group (pqac-00000006, pqac-00000018) | Wang et al. 2024, https://doi.org/10.3390/ijms25052734; Guignabert et al. 2024, https://doi.org/10.1183/13993003.01095-2024; Kovacs et al. 2024, https://doi.org/10.1183/13993003.01324-2024 |
| **KCNK3** | Ion channel (two-pore K+ channel) | Included in definitive-evidence PAH gene list (pqac-00000019) | Not explicitly stated in current evidence | No quantitative frequency retrieved in current evidence (pqac-00000019) | Kovacs et al. 2024, https://doi.org/10.1183/13993003.01324-2024 |
| **TBX4** | Development / transcription factor; lung development | Included in definitive-evidence list; associated with developmental abnormalities and pediatric PAH enrichment; may show hip/knee issues and bronchial abnormalities (pqac-00000019, pqac-00000016, pqac-00000006) | **AD with incomplete penetrance and variable expressivity** (pqac-00000016) | Pathogenic variants reported in **3–7%** of CHD-APAH for SOX17, not TBX4; for TBX4 only qualitative pediatric enrichment supported in current evidence (pqac-00000016) | Eichstaedt et al. 2023, https://doi.org/10.1183/13993003.01471-2022; Kovacs et al. 2024, https://doi.org/10.1183/13993003.01324-2024; Guignabert et al. 2024, https://doi.org/10.1183/13993003.01095-2024 |
| **SOX17** | Development / transcription factor; vascular and cardiac development | Included in definitive-evidence list; described in FPAH/IPAH and especially CHD-associated PAH; associated CT findings may include dilated/tortuous pulmonary vessels, ground-glass opacities, haemoptysis (pqac-00000019, pqac-00000016) | Not explicitly stated in current evidence | In CHD-associated PAH, pathogenic variants identified in **3–7%** of patients (pqac-00000016) | Eichstaedt et al. 2023, https://doi.org/10.1183/13993003.01471-2022; Kovacs et al. 2024, https://doi.org/10.1183/13993003.01324-2024 |
| **KDR** | Development / angiogenesis; VEGF receptor 2 | Included in definitive-evidence list; protein-truncating variants linked to PAH with interstitial lung disease and low DLCO (pqac-00000019, pqac-00000016) | Not explicitly stated in current evidence | No quantitative frequency retrieved in current evidence (pqac-00000016, pqac-00000019) | Eichstaedt et al. 2023, https://doi.org/10.1183/13993003.01471-2022; Kovacs et al. 2024, https://doi.org/10.1183/13993003.01324-2024 |
| **ATP13A3** | Membrane ATPase / transporter | Included in definitive-evidence list; among highest-incidence variants in one Taiwanese idiopathic/heritable PAH WES cohort (pqac-00000019, pqac-00000018) | Not explicitly stated in current evidence | Reported among highest-incidence variant genes in a **69-patient** cohort, but no percentage given in excerpt (pqac-00000018) | Wang et al. 2024, https://doi.org/10.3390/ijms25052734; Kovacs et al. 2024, https://doi.org/10.1183/13993003.01324-2024 |
| **CAV1** | Caveolae / membrane signaling | Included in definitive-evidence list; also grouped among genes connected to BMPR-II signaling in 7th WSPH pathology review (pqac-00000019, pqac-00000006) | Not explicitly stated in current evidence | No quantitative frequency retrieved in current evidence (pqac-00000006, pqac-00000019) | Kovacs et al. 2024, https://doi.org/10.1183/13993003.01324-2024; Guignabert et al. 2024, https://doi.org/10.1183/13993003.01095-2024 |
| **EIF2AK4** | Integrated stress response kinase; PVOD/PCH gene | Included in definitive-evidence list for PAH gene-disease relationship review/guidelines, but clinically emphasized for **heritable PVOD/PCH** rather than classic HPAH; genetic testing can identify misclassified PVOD/PCH and prompt early transplant referral (pqac-00000019, pqac-00000016) | **AR** for heritable PVOD/PCH due to **biallelic** variants; semidominant/AR note also mentioned generally for some PAH genes (pqac-00000016) | Biallelic EIF2AK4 variants represent **at least 25% of PVOD/PCH cases** (pqac-00000016) | Eichstaedt et al. 2023, https://doi.org/10.1183/13993003.01471-2022; Kovacs et al. 2024, https://doi.org/10.1183/13993003.01324-2024 |


*Table: This table summarizes the HPAH-definitive or clearly supported genes, their functional classes, inheritance notes, and the main quantitative facts retrievable from the current evidence corpus. It is useful for quickly populating a disease knowledge base with high-confidence gene-level information while distinguishing classic HPAH genes from EIF2AK4-associated PVOD/PCH.*