RAP1A

protein-coding

RAP1A, member of RAS oncogene family, the group of RAS type GTPase family

Gene summary

This gene encodes a member of the Ras family of small GTPases. The encoded protein undergoes a change in conformational state and activity, depending on whether it is bound to GTP or GDP. This protein is activated by several types of guanine nucleotide exchange factors (GEFs), and inactivated by two groups of GTPase-activating proteins (GAPs). The activation status of the encoded protein is therefore affected by the balance of intracellular levels of GEFs and GAPs. The encoded protein regulates signaling pathways that affect cell proliferation and adhesion, and may play a role in tumor malignancy. Pseudogenes of this gene have been defined on chromosomes 14 and 17. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

MANE transcript

NM_002884.4

Inheritance

ClinVar variants

U:14B:7

Top phenotype

RAP1A-related disorder

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr1:111,542,218-111,716,691

External References & Databases

Ensembl (ENSG00000116473)

Transcript & Mutation Effects

hg38 • Region Span ~174.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Kabuki syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0016512

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RAP1A variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 16

not providedTotal: 10

RAP1A-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002884.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	7 clinvar		8
missense			8 clinvar			8
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	0	0	14	7	0	21

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 88 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002884.4	RefSeq	NP_002875.1	6	MANE Select
ENST00000369709.4	Ensembl	ENSP00000358723.3	6	MANE Select
NM_001010935.3	RefSeq	NP_001010935.1	6	Standard
NM_001291896.3	RefSeq	NP_001278825.1	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
rap1aa	Danio rerio	Structure: whole organism Quality: increased curvature abnormal

Gene / Model

Organism

Observed Phenotype

rap1aa

Danio rerio

Structure: whole organism

Quality: increased curvature

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Platelet activation - Homo sapiens (human)
Focal adhesion - Homo sapiens (human)
Renal cell carcinoma - Homo sapiens (human)
Long-term potentiation - Homo sapiens (human)
Neurotrophin signaling pathway - Homo sapiens (human)

Biological Process

signal transduction
positive regulation of neuron projection development
protein transport
microvillus assembly
Rap protein signal transduction

Molecular Function

GTPase activity
protein binding
GTP binding
protein transporter activity
Rap guanyl-nucleotide exchange factor activity

Cellular Component

cytoplasm
early endosome
late endosome
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000369709
Coding exons: 6
Length: 174474
Individuals with no LoFs: 125636
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125642
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.36	32	97.7	0.327	0.00000523	1199
Missense (PolyPhen)		4	33.554	0.11921		442
Synonymous	0.860	31	37.7	0.822	0.00000228	332
Loss of Function	2.63	2	11.7	0.171	5.78e-7	147

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000048	0.000046	rare
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Induces morphological reversion of a cell line transformed by a Ras oncogene. Counteracts the mitogenic function of Ras, at least partly because it can interact with Ras GAPs and RAF in a competitive manner. Together with ITGB1BP1, regulates KRIT1 localization to microtubules and membranes. Plays a role in nerve growth factor (NGF)-induced neurite outgrowth. Plays a role in the regulation of embryonic blood vessel formation. Involved in the establishment of basal endothelial barrier function. May be involved in the regulation of the vascular endothelial growth factor receptor KDR expression at endothelial cell-cell junctions. {ECO:0000269|PubMed:17916086, ECO:0000269|PubMed:21840392}.;

Recessive Scores

pRec: 0.281

Intolerance Scores

RVIS EVS: -0.08
RVIS percentile EVS: 47.79

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.970

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Low	Low	Low
Primary Immunodeficiency	Medium	Low	Medium
Cancer	Low	Low	Low