RIT1
Chr 1ADRas like without CAAX 1
Also known as: NS8, RIBB, RIT, ROC1
The protein functions as a Ras-related GTPase that regulates p38 MAPK signaling cascades, promotes neuronal development and regeneration with nerve growth factor, and controls T-lymphocyte differentiation and survival during thymocyte development. Mutations cause Noonan syndrome 8, a multisystem disorder typically presenting in infancy with characteristic facial features, short stature, and cardiac abnormalities. Inheritance is autosomal dominant.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Moderately missense-constrained (top ~2.5%)
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
240 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 12 | 9 | 0 | 21 |
Likely Pathogenic | 0 | 15 | 1 | 0 | 16 |
VUS | 6 | 101 | 9 | 1 | 117 |
Likely Benign | 0 | 0 | 29 | 45 | 74 |
Benign | 0 | 1 | 2 | 1 | 4 |
Conflicting | — | 4 | |||
| Total | 6 | 129 | 50 | 47 | 236 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
RIT1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Study of the Thyroid Function and Echostructural Morphology in Patients Affected With Rasopathies (ECORAS2023)
RECRUITINGTreatment Strategies and Survival Outcome for Non-small Cell Lung Cancer With Oncogenic Mutation
RECRUITINGExternal Resources
Links to major genomics databases and tools