RAP2A

Chr 13

RAP2A, member of RAS oncogene family

RAP2A encodes a small GTP-binding protein that cycles between active and inactive forms to regulate neuronal dendrite development, cytoskeletal rearrangements, cell migration, and cell adhesion through interactions with downstream effectors including MAP4K4 and TNIK. Mutations cause autosomal dominant neurodevelopmental disorder with epilepsy, affecting the nervous system primarily. The gene is highly constrained against loss-of-function variants (pLI = 0.85, LOEUF = 0.48), indicating that complete loss of protein function is likely not tolerated.

ResearchSummary from RefSeq, UniProt

Small GTP-binding protein which cycles between a GDP-bound inactive and a GTP-bound active form (PubMed:14966141, PubMed:15342639, PubMed:16246175, PubMed:16540189, PubMed:18930710, PubMed:20159449, PubMed:35293963). In its active form interacts with and regulates several effectors including MAP4K4, MINK1 and TNIK (PubMed:14966141, PubMed:15342639, PubMed:18930710, PubMed:20159449). Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development (PubMed:20159449). More generally, it is part of several signaling cascades and regulates cytoskeletal rearrangements, cell migration, cell adhesion and cell spreading (PubMed:14966141, PubMed:15342639, PubMed:16246175, PubMed:16540189, PubMed:18930710, PubMed:20159449, PubMed:35293963)

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.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.48

LOEUF

GOF

Mechanism· predicted

Some data sources returned errors (2)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.48LOEUF

pLI 0.851

Z-score 2.32

OE 0.00 (0.00–0.48)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.56Z-score

OE missense 0.31 (0.24–0.41)

34 obs / 109.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.48)

0≤0.351.4

Missense OE?0.31 (0.24–0.41)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 0 / 6.2Missense obs/exp: 34 / 109.4Syn Z: -1.04

Background carrier burden — how many people carry a rare variant somewhere in RAP2A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 1,300

122 rare PASS variants

Rare truncating (LoF)

1 in 49,000

12 rare PASS variants

Rare synonymous (reference)

1 in 370

120 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RAP2A. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 8 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 1,300	1 in 43,000
South Asian	~43k	1 in 2,700	none seen
Remaining (unassigned)	~30k	1 in 1,800	none seen
European (Finnish)	~27k	1 in 5,300	none seen
Admixed American	~22k	1 in 1,600	≈ 1 in 22,000
African / African American	~21k	1 in 2,100	none seen
East Asian	~20k	1 in 490	≈ 1 in 20,000
Ashkenazi Jewish	~13k	≈ 1 in 3,300	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 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓