RALGAPA1

Chr 14

Ral GTPase activating protein catalytic subunit alpha 1

Also known as: GARNL1, GRIPE, NEDHRIT, RalGAPalpha1, TULIP1, p240

NCBI Gene: 253959ENSG00000174373UniProt: Q6GYQ0

This gene encodes a major subunit of the RAL-GTPase activating protein. A similar protein in mouse binds E12, a transcriptional regulator of immunoglobulin genes. The mouse protein also functions in skeletal muscle by binding to the regulatory 14-3-3 proteins upon stimulation with insulin or muscle contraction. A pseudogene of this gene has been identified on chromosome 9. [provided by RefSeq, Oct 2016]

Primary Disease Associations & Inheritance

UniProtNeurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation
333
ClinVar variants
39
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— RALGAPA1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
39 Pathogenic / Likely Pathogenic· 244 VUS of 333 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.23LOEUF
pLI 1.000
Z-score 8.03
OE 0.15 (0.10–0.23)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
3.53Z-score
OE missense 0.69 (0.65–0.74)
716 obs / 1035.4 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.15 (0.10–0.23)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.69 (0.65–0.74)
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.0.95
0≤1.21.6
LoF obs/exp: 16 / 104.6Missense obs/exp: 716 / 1035.4Syn Z: 0.77

ClinVar Variant Classifications

333 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic34
Likely Pathogenic5
VUS244
Likely Benign37
Benign11
Conflicting2
34
Pathogenic
5
Likely Pathogenic
244
VUS
37
Likely Benign
11
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
1
31
0
34
Likely Pathogenic
2
0
3
0
5
VUS
1
232
11
0
244
Likely Benign
0
10
3
24
37
Benign
0
3
6
2
11
Conflicting
—2
Total52465426333

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

RALGAPA1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

RALGAPA1-related neurodevelopmental disorder

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Mycobacterium tuberculosis infection may increase the degrees of malignancy in lung adenocarcinoma.
Li S et al.·Front Immunol
2025
Bi-allelic Variants in RALGAPA1 Cause Profound Neurodevelopmental Disability, Muscular Hypotonia, Infantile Spasms, and Feeding Abnormalities.
Wagner M et al.·Am J Hum Genet
2020
RALGAPA1 Deletion in Belgian Shepherd Dogs with Cerebellar Ataxia.
Christen M et al.·Genes (Basel)
2023
An early onset benign myopathy with glycogen storage caused by a de novo 1.4 Mb-deletion of chromosome 14.
Severa G et al.·Neuromuscul Disord
2023Case report
A DNA methylation signature discriminates between excellent and non-response to lithium in patients with bipolar disorder type 1.
Marie-Claire C et al.·Sci Rep
2020Cohort
TULIP1 (RALGAPA1) haploinsufficiency with brain development delay.
Shimojima K et al.·Genomics
2009Case report
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools