RAB11B

Chr 19

RAB11B, member RAS oncogene family

Also known as: H-YPT3, NDAGSCW

NCBI Gene: 9230 ENSG00000185236 UniProt: Q15907

The protein regulates recycling endosome membrane trafficking and exocytotic/endocytotic pathways. Dominant-negative mutations cause autosomal dominant neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter. The pathogenic mechanism involves dominant-negative effects that disrupt normal endosomal trafficking functions.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The Ras superfamily of small GTP-binding proteins, which includes the Ras (see MIM 190020), Ral (see MIM 179550), Rho (see MIM 165390), Rap (see MIM 179520), and Rab (see MIM 179508) families, is involved in controlling a diverse set of essential cellular functions. The Rab family, including RAB11B, appears to play a critical role in regulating exocytotic and endocytotic pathways (summary by Zhu et al., 1994 [PubMed 7811277]).[supplied by OMIM, Nov 2010]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.64

Clinical Summary— RAB11B

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.20) despite low pLI — interpret in context.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 77 VUS of 264 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.64LOEUF

pLI 0.444

Z-score 2.31

OE 0.20 (0.08–0.64)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.48Z-score

OE missense 0.44 (0.36–0.53)

67 obs / 153.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.20 (0.08–0.64)

0≤0.351.4

Missense OE?0.44 (0.36–0.53)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 2 / 9.8Missense obs/exp: 67 / 153.6Syn Z: -0.18

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongRAB11B-related intellectual disabilityOTHERAD

This gene — mechanism propensity

0.76top 25%

GOF

0.6832th %ile

LOF

0.3746th %ile

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

DNprediction above median · 1 literature citation

GOFprediction above median

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

DNLamers et al. (2017) concluded that the mutations act in a dominant-negative manner to alter GDP/GTP binding, thus inactivating the protein and causing alterations in binding to certain guanine nucleotide exchange factors (GEFs), as well as protein mislocalization, which may have additional adverse 1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 29106825 ↗

ClinVar Variant Classifications

264 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic5

VUS77

Likely Benign136

Benign34

Conflicting7

Pathogenic

Likely Pathogenic

VUS

136

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	0	5	0	0	5
VUS	5	63	9	0	77
Likely Benign	1	15	47	73	136
Benign	0	3	22	9	34
Conflicting	—				7
Total	6	87	78	82	260

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

View in ClinVar →

5 pathogenic / likely-pathogenic (of 7) ClinVar copy-number / structural variants overlap RAB11B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →