RRAGA

Chr 9

Ras related GTP binding A

Also known as: FIP-1, FIP1, RAGA

NCBI Gene: 10670 ENSG00000155876 UniProt: Q7L523 OMIM: 612194

The protein is a guanine nucleotide-binding protein that regulates mTORC1 signaling in response to amino acid availability by forming heterodimeric complexes at the lysosome and recruiting mTORC1 for activation. Mutations in this gene cause autosomal recessive epileptic encephalopathy and neurodevelopmental disorders with early infantile onset. The gene shows moderate constraint to loss-of-function variants, and affected children typically present with seizures, developmental delays, and neurological regression in the first months of life.

OMIM ResearchSummary from RefSeq, UniProt

Enables several functions, including GTP binding activity; protein dimerization activity; and ubiquitin protein ligase binding activity. Involved in several processes, including cellular response to amino acid starvation; positive regulation of TORC1 signaling; and tumor necrosis factor-mediated signaling pathway. Located in GATOR1 complex; lysosome; and nucleoplasm. Part of FNIP-folliculin RagC/D GAP. Is active in lysosomal membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.71

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.71LOEUF

pLI 0.356

Z-score 2.13

OE 0.23 (0.09–0.71)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.99Z-score

OE missense 0.36 (0.29–0.45)

63 obs / 173.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.23 (0.09–0.71)

0≤0.351.4

Missense OE?0.36 (0.29–0.45)

0≤0.61.4

Synonymous OE?1.27

0≤1.21.6

LoF obs/exp: 2 / 8.8Missense obs/exp: 63 / 173.7Syn Z: -1.75

Background carrier burden — how many people carry a rare variant somewhere in RRAGA?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 400

236 rare PASS variants

Rare truncating (LoF)

1 in 8,100

34 rare PASS variants

Rare synonymous (reference)

1 in 270

203 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RRAGA. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 360	1 in 14,000
South Asian	~43k	1 in 770	1 in 2,400
Remaining (unassigned)	~30k	1 in 600	≈ 1 in 30,000
European (Finnish)	~27k	1 in 470	none seen
Admixed American	~22k	1 in 420	1 in 2,300
African / African American	~21k	1 in 670	1 in 3,500
East Asian	~20k	1 in 590	1 in 2,300
Ashkenazi Jewish	~13k	≈ 1 in 6,500	none seen
Middle Eastern	~2,884	≈ 1 in 1,400	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓