RAP1B

Chr 12AD

RAP1B, member of RAS oncogene family

Also known as: K-REV, RAL1B, THC11

NCBI Gene: 5908 ENSG00000127314 UniProt: P61224 OMIM: 179530

RAP1B encodes a small GTP-binding protein that regulates integrin-mediated cell signaling, platelet function, and endothelial cell polarity and barrier function. Mutations cause thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants (pLI 0.91, LOEUF 0.39), indicating that functional copies are essential for normal development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the RAS-like small GTP-binding protein superfamily. Members of this family regulate multiple cellular processes including cell adhesion and growth and differentiation. This protein localizes to cellular membranes and has been shown to regulate integrin-mediated cell signaling. This protein also plays a role in regulating outside-in signaling in platelets. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 3, 5, 6 and 9. [provided by RefSeq, Oct 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic faciesMIM #620654

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies · AD · ClinGen 2026

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

0.39

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — RAP1B

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.39LOEUF

pLI 0.910

Z-score 2.96

OE 0.08 (0.03–0.39)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.60Z-score

OE missense 0.25 (0.18–0.35)

24 obs / 95.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.08 (0.03–0.39)

0≤0.351.4

Missense OE?0.25 (0.18–0.35)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 1 / 12.1Missense obs/exp: 24 / 95.5Syn Z: -0.45

Background carrier burden — how many people carry a rare variant somewhere in RAP1B?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 1,700

123 rare PASS variants

Rare truncating (LoF)

1 in 7,900

18 rare PASS variants

Rare synonymous (reference)

1 in 310

85 rare PASS variants

Rare missense and truncating variants are carried at similar rates in RAP1B; this gene does not show strong loss-of-function constraint by this measure. 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 1,700	1 in 9,400
South Asian	~43k	1 in 1,500	≈ 1 in 14,000
Remaining (unassigned)	~30k	1 in 2,000	≈ 1 in 15,000
European (Finnish)	~27k	1 in 2,400	none seen
Admixed American	~22k	1 in 730	≈ 1 in 4,500
African / African American	~21k	1 in 960	≈ 1 in 4,800
East Asian	~20k	1 in 2,200	≈ 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): 4 of 6 coding exons well covered in gnomAD exomes; exons 3, 5 marginal. Genomes: all 6.? see exons ↓