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In a consecutive single-centre series of 37 positive clinical genetic tests performed in 2021\u20132023, a skewed distribution pattern was noted, with 30 of 32 variants reported only once, but ACVRL1 c.1231C&gt;T (p.Arg411Trp) identified as the disease-causal gene in five different HHT families. In the same centre\u2019s non-overlapping 1992\u20132020 series where 110\/134 (82.1%) HHT-causal variants were reported only once, ACVRL1 c.1231C&gt;T (p.Arg411Trp) was identified in nine further families. In a 14-country, four-continent HHT Mutation Database where 181\/250 (72.4%) HHT-causal variants were reported only once, ACVRL1 c.1231C&gt;T (p.Arg411Trp) was reported by 12 different laboratories, the adjacent ACVRL1 c.1232G&gt;A (p.Arg411Gln) by 14, and ACVRL1 c.1120C&gt;T (p.Arg374Trp) by 18. Unlike the majority of HHT-causal ACVRL1 variants, these encode ALK1 protein that reaches the endothelial cell surface but fails to signal. Six variants of this type were present in the three series and were reported 6.8\u201325.5 (mean 8.9) times more frequently than the other ACVRL1 missense variants (all p-values &lt; 0.0039). Noting lower rates of myocardial infarction reported in HHT, we explore potential mechanisms, including a selective paradigm relevant to ALK1\u2032s role in the initiating event of atherosclerosis, where a plausible dominant negative effect of these specific variants can be proposed. In conclusion, there is an ~9-fold excess of kinase-inactive, cell surface-expressed ACVRL1\/ALK1 pathogenic missense variants in HHT. The findings support further examination of differential clinical and cellular phenotypes by HHT causal gene molecular subtypes.<\/jats:p>","DOI":"10.3390\/jcm13010250","type":"journal-article","created":{"date-parts":[[2023,12,31]],"date-time":"2023-12-31T06:00:21Z","timestamp":1704002421000},"page":"250","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Pathogenic Variant Frequencies in Hereditary Haemorrhagic Telangiectasia Support Clinical Evidence of Protection from Myocardial Infarction"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7903-3005","authenticated-orcid":false,"given":"Kinshuk","family":"Jain","sequence":"first","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5072-2229","authenticated-orcid":false,"given":"Sarah C.","family":"McCarley","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0630-2598","authenticated-orcid":false,"given":"Ghazel","family":"Mukhtar","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Ferlin","sequence":"additional","affiliation":[{"name":"Clinical Genetics and Genomics Laboratory, Royal Brompton Hospital, Guy\u2019s and St Thomas\u2019 NHS Trust, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Fleming","sequence":"additional","affiliation":[{"name":"Clinical Genetics and Genomics Laboratory, Royal Brompton Hospital, Guy\u2019s and St Thomas\u2019 NHS Trust, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7780-4707","authenticated-orcid":false,"given":"Deborah J.","family":"Morris-Rosendahl","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, London W12 0NN, UK"},{"name":"Clinical Genetics and Genomics Laboratory, Royal Brompton Hospital, Guy\u2019s and St Thomas\u2019 NHS Trust, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9007-5775","authenticated-orcid":false,"given":"Claire L.","family":"Shovlin","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, London W12 0NN, UK"},{"name":"Specialist Medicine, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London W12 0HS, UK"},{"name":"Social, Genetic and Environmental Determinants of Health, NIHR Imperial Biomedical Research Centre, London W2 1NY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,31]]},"reference":[{"key":"ref_1","first-page":"856","article-title":"A case of Haemophilia complicated with Multiple Naevi","volume":"2","author":"Legg","year":"1876","journal-title":"Lancet"},{"key":"ref_2","first-page":"769","article-title":"Epistaxis as an indication of impaired nutrition, and of degeneration of the vascular system","volume":"1","author":"Sutton","year":"1864","journal-title":"Med. 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