RAP1GAP2

Chr 17

RAP1 GTPase activating protein 2

Also known as: GARNL4, RAP1GA3

NCBI Gene: 23108 ENSG00000132359 UniProt: Q684P5 OMIM: 618714

The protein is a GTPase-activating protein that inactivates RAP1A by converting it from GTP-bound to GDP-bound state and regulates platelet dense granule secretion at sites of vascular injury. Mutations cause autosomal dominant intellectual disability with variable features that may include developmental delay and neurological abnormalities. This gene is highly constrained against loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a GTPase-activating protein that activates the small guanine-nucleotide-binding protein Rap1 in platelets. The protein interacts with synaptotagmin-like protein 1 and Rab27 and regulates secretion of dense granules from platelets at sites of endothelial damage. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.32

Clinical Summary— RAP1GAP2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

86 VUS of 129 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.32LOEUF

pLI 0.969

Z-score 4.97

OE 0.17 (0.10–0.32)

Highly constrained

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

Missense Constraint?

2.23Z-score

OE missense 0.70 (0.64–0.77)

307 obs / 438.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.17 (0.10–0.32)

0≤0.351.4

Missense OE?0.70 (0.64–0.77)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 7 / 41.6Missense obs/exp: 307 / 438.2Syn Z: 0.78

This gene — mechanism propensity

0.4785th %ile

GOF

0.5268th %ile

LOF

0.65top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.32

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

129 submitted variants in ClinVar

ClinVar

Classification Summary

VUS86

Likely Benign6

Benign3

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	86	0	0	86
Likely Benign	4	0	2	6
Benign	1	1	1	3
Total	91	1	3	95

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

View in ClinVar →

61 pathogenic / likely-pathogenic (of 77) ClinVar copy-number / structural variants overlap RAP1GAP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →