RIT1

Chr 1AD

Ras like without CAAX 1

NCBI Gene: 64919ENSG00000143622UniProt: Q9C0K0

Key regulator of both differentiation and survival of T-lymphocytes during thymocyte development in mammals. Essential in controlling the responsiveness of hematopoietic stem cells to chemotactic signals by modulating the expression of the receptors CCR7 and CCR9, which direct the movement of progenitor cells from the bone marrow to the thymus (PubMed:27959755). Is a regulator of IL2 promoter and enhances IL2 expression in activated CD4(+) T-lymphocytes (PubMed:16809611). Tumor-suppressor that represses transcription through direct, TFCOUP2-independent binding to a GC-rich response element (By similarity). May also function in the P53-signaling pathway (By similarity)

Primary Disease Associations & Inheritance

Noonan syndrome 8MIM #615355
AD
UniProtImmunodeficiency 49, severe combined
UniProtIntellectual developmental disorder with speech delay, dysmorphic facies, and T-cell abnormalities
438
ClinVar variants
54
Pathogenic / LP
0.13
pLI score
2
Active trials
Clinical Summary— RIT1
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.
📋
ClinVar Variants
54 Pathogenic / Likely Pathogenic· 207 VUS of 438 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.65LOEUF
pLI 0.133
Z-score 2.51
OE 0.28 (0.14–0.65)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.08Z-score
OE missense 0.52 (0.43–0.63)
75 obs / 145.4 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.28 (0.14–0.65)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.52 (0.43–0.63)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
0≤1.21.6
LoF obs/exp: 4 / 14.2Missense obs/exp: 75 / 145.4Syn Z: 0.09

ClinVar Variant Classifications

438 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic32
Likely Pathogenic22
VUS207
Likely Benign139
Benign15
Conflicting19
32
Pathogenic
22
Likely Pathogenic
207
VUS
139
Likely Benign
15
Benign
19
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
18
14
0
32
Likely Pathogenic
0
19
3
0
22
VUS
7
172
27
1
207
Likely Benign
0
1
58
80
139
Benign
0
1
13
1
15
Conflicting
—19
Total721111582434

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.

Gene2Phenotype Curations

RIT1-related Noonan syndrome

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. DisordersSkinCardiac
G2P ↗
missense variant

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Noonan syndrome 8

MIM #615355

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Rare molecular subtypes of lung cancer.
Harada G et al.·Nat Rev Clin Oncol
2023Review
Clinical features and molecular genetics of patients with RASopathies: expanding the phenotype with rare genes and novel variants.
Yılmaz Uzman C et al.·Eur J Pediatr
2024Cohort
De novo variants underlying monogenic syndromes with intellectual disability in a neurodevelopmental cohort from India.
Pande S et al.·Eur J Hum Genet
2024Cohort
The molecular functions of RIT1 and its contribution to human disease.
Van R et al.·Biochem J
2020Review
Mutant RIT1 cooperates with YAP to drive an EMT-like lung cancer state.
Rominger MC et al.·Cell Rep
2025
Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition.
Kapp FG et al.·Angiogenesis
2024
RIT1 oncoproteins escape LZTR1-mediated proteolysis.
Castel P et al.·Science
2019
Designing Myeloid Gene Panels.
Zhao F et al.·Arch Pathol Lab Med
2022
Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation.
Kouz K et al.·Genet Med
2016Cohort
Ras-MAPK pathway in patients with lupus nephritis.
Zhang C et al.·Lupus Sci Med
2025Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Non Small Cell Lung CancerEGFR Gene MutationALK Gene Mutation

Treatment Strategies and Survival Outcome for Non-small Cell Lung Cancer With Oncogenic Mutation

RECRUITING
NCT04322890Phase PHASE2Hunan Province Tumor HospitalStarted 2020-04-16
OsimertinibAlectinib 150 MGCrizotinib 250 MG
RASopathy

Study of the Thyroid Function and Echostructural Morphology in Patients Affected With Rasopathies (ECORAS2023)

RECRUITING
NCT06489067University of Bari Aldo MoroStarted 2024-01-15

External Resources

Links to major genomics databases and tools