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…

MultiplemechanismADLOEUF 0.391 OMIM phenotype

Clinical Summary— RAP1B

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Gene-Disease Validity (ClinGen)

thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.91). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 11 VUS of 57 total submissions

Explore recent and relevant literature in Research Assistant →

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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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedRAP1B-related developmental disorderOTHERAD

This gene — mechanism propensity

0.6065th %ile

GOF

0.7030th %ile

LOF

0.52top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

LOFLOEUF 0.39

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFWe report a 23-year-old male with a novel, de novo RAP1B gain-of-function variant identified on genome sequencing.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 35451551 ↗

ClinVar Variant Classifications

57 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic2

VUS11

Likely Benign7

Benign14

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	4	0	0	4
Likely Pathogenic	0	2	0	0	2
VUS	1	9	1	0	11
Likely Benign	0	0	2	5	7
Benign	0	0	13	1	14
Conflicting	—				1
Total	1	15	16	6	39

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap RAP1B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →