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Previously, we established\n                    <jats:italic>CACNA1I<\/jats:italic>\n                    , the gene coding for Ca\n                    <jats:sub>V<\/jats:sub>\n                    3.3, as a disease gene for neurodevelopmental disease with or without epilepsy. Here we report three newly identified activation-gate-modifying heterozygous missense variants of\n                    <jats:italic>CACNA1I<\/jats:italic>\n                    , found in four unrelated patients with neurodevelopmental disease with or without seizures. One of these variants, p.(Met1425Val), is an amino-acid substitution at the same position as previously published variant p.(Met1425Ile). Notably, the other two variants studied here are also a pair of two different substitutions of the same amino acid: p.(Ala398Val) and p.(Ala398Glu). By using site-directed mutagenesis, voltage-clamp electrophysiology, computational modelling of neuronal excitability, and structure modelling, we found that the two substitutions of M1425 both result in a gain of channel function including left-shifted voltage-dependence of activation and inactivation, slowed inactivation and deactivation kinetics, and increased neuronal excitability. Remarkably, the two substitutions of A398 show opposite effects on channel function. While substitution A398E leads to a gain of channel function, A398V results in decreased current density, accelerated gating kinetics, and a decreased neuronal excitability. The lack of seizures in the two independent p.(Ala398Val) patients correlates with the absence of increased neuronal excitability in this variant. This is the first report of a gate-modifying Ca\n                    <jats:sub>V<\/jats:sub>\n                    3.3 channel variant with partial loss-of-function effects associated with developmental delay and intellectual disability without seizures. Our study corroborates the role of Ca\n                    <jats:sub>V<\/jats:sub>\n                    3.3 dysfunction in the etiology of neurodevelopmental disorders. Moreover, our data suggest that substantial gain-of-function of Ca\n                    <jats:sub>V<\/jats:sub>\n                    3.3 leads to the development of seizures, whereas both gain- and loss-of-function variants of\n                    <jats:italic>CACNA1I<\/jats:italic>\n                    can cause neurodevelopmental disease.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1011828","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T17:54:40Z","timestamp":1755539680000},"page":"e1011828","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Two pairs of CACNA1I (CaV3.3) variants with opposite effects on channel function cause neurodevelopmental disorders of varying severity"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0829-5865","authenticated-orcid":true,"given":"Yousra","family":"El Ghaleb","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica L.","family":"Fern\u00e1ndez-Quintero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9629-2073","authenticated-orcid":true,"given":"Marta","family":"Campiglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3660-6138","authenticated-orcid":true,"given":"Petronel","family":"Tuluc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann-Sophie","family":"H\u00f6ing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanny","family":"Kort\u00fcm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahdi M.","family":"Motazacker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris E.","family":"Jansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0119-6928","authenticated-orcid":true,"given":"Mariet W.","family":"Elting","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4903-8232","authenticated-orcid":true,"given":"Astrid S.","family":"Plomp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Lena M.","family":"Fischer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria M.","family":"Siu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8494-8963","authenticated-orcid":true,"given":"Kerstin","family":"Kutsche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5255-4705","authenticated-orcid":true,"given":"Bernhard E.","family":"Flucher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,8,18]]},"reference":[{"issue":"3","key":"pgen.1011828.ref001","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1021\/acschemneuro.9b00031","article-title":"T-Type Channel Druggability at a Crossroads","volume":"10","author":"N Weiss","year":"2019","journal-title":"ACS Chem 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