RAB39B

Summary

RAB39B (RAB39B, member RAS oncogene family, HGNC:16499) is a protein-coding gene on chromosome Xq28, encoding Ras-related protein Rab-39B (Q96DA2). The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the Rab family of proteins. Rab proteins are small GTPases that are involved in vesicular trafficking. Mutations in this gene are associated with X-linked cognitive disability.

Source: NCBI Gene 116442 — RefSeq curated summary.

At a glance

• Gene–disease (curated): early-onset parkinsonism-intellectual disability syndrome (Definitive, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 114 total — 6 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 32
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_171998

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16499
Approved symbol	RAB39B
Name	RAB39B, member RAS oncogene family
Location	Xq28
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000155961
Ensembl biotype	protein_coding
OMIM	300774
Entrez	116442

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000369454

RefSeq mRNA: 1 — MANE Select: NM_171998 NM_171998

CCDS: CCDS14766

Canonical transcript exons

ENST00000369454 — 2 exons

Exon	Start	End
ENSE00001450068	155258235	155261229
ENSE00001450069	155264074	155264491

Expression profiles

Bgee: expression breadth ubiquitous, 172 present calls, max score 95.50.

FANTOM5 (CAGE): breadth broad, TPM avg 4.4021 / max 80.0612, expressed in 904 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
201082	4.4021	904

Top tissues by expression

248 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	95.50	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.02	gold quality
middle temporal gyrus	UBERON:0002771	87.34	gold quality
cortical plate	UBERON:0005343	86.02	gold quality
primary visual cortex	UBERON:0002436	85.84	gold quality
islet of Langerhans	UBERON:0000006	83.58	gold quality
Brodmann (1909) area 46	UBERON:0006483	83.36	gold quality
prefrontal cortex	UBERON:0000451	82.61	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	81.94	gold quality
Brodmann (1909) area 9	UBERON:0013540	81.87	gold quality
superior frontal gyrus	UBERON:0002661	81.49	gold quality
entorhinal cortex	UBERON:0002728	81.01	gold quality
occipital lobe	UBERON:0002021	80.73	gold quality
neocortex	UBERON:0001950	80.70	gold quality
frontal cortex	UBERON:0001870	80.67	gold quality
cerebral cortex	UBERON:0000956	80.63	gold quality
ganglionic eminence	UBERON:0004023	79.92	gold quality
anterior cingulate cortex	UBERON:0009835	79.65	gold quality
postcentral gyrus	UBERON:0002581	79.32	gold quality
cerebellar cortex	UBERON:0002129	78.71	gold quality
cerebellar hemisphere	UBERON:0002245	78.70	gold quality
Ammon’s horn	UBERON:0001954	78.64	gold quality
cerebellum	UBERON:0002037	78.48	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	78.27	gold quality
forebrain	UBERON:0001890	78.26	gold quality
hypothalamus	UBERON:0001898	78.09	gold quality
brain	UBERON:0000955	78.02	gold quality
right frontal lobe	UBERON:0002810	77.75	gold quality
temporal lobe	UBERON:0001871	77.36	gold quality
right hemisphere of cerebellum	UBERON:0014890	77.15	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.55

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

130 targeting RAB39B, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 21)

• RAB39B was expressed in a variety of human tissues and located in human chromosome Xq28. (PMID:12438742)
• These results demonstrate developmental and functional neuronal alteration as a consequence of downregulation of RAB39B and emphasize the critical role of vesicular trafficking in the development of neurons and human intellectual abilities. (PMID:20159109)
• Data indicate that myosin Va interacted with multiple new Rab subfamilies including Rab6, Rab14 and Rab39B. (PMID:24006491)
• increased dosage of RAB39B causes a disturbed neuronal development leading to cognitive impairment (PMID:24357492)
• The loss of RAB39B results in dysregulation of alpha-synuclein homeostasis and a spectrum of neuropathological features that implicate RAB39B in the pathogenesis of Parkinson disease and potentially other neurodegenerative disorders. (PMID:25434005)
• RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition (PMID:25784538)
• It plays little or no role in the development of PD in Chinese population. (PMID:26163985)
• RAB39B is an essential regulator of vesicular-trafficking in clinically typical Parkinson’s disease (PMID:26399558)
• RAB39B mutations are a rare finding in Parkinson disease patients (PMID:26739247)
• Direct sequencing analysis of all coding exons and exon-intron boundaries was performed to detect small sequence alterations in RAB39B gene (PMID:27036214)
• This study identified two patients carrying a variant in RAB39B out of 344 male patients with Parkinsonsim. (PMID:27448726)
• RAB39B mutations are not a common cause of Parkinson’s disease or dementia with Lewy bodies in Caucasian population (PMID:27459931)
• results suggest that RAB39B mutation is very rare in familial PD and may not be a major cause of familial PD in the Chinese Han Population (PMID:27694831)
• RAB39B mutations are not a common cause of early-onset or familial PD in our Taiwanese population. (PMID:27838047)
• X-linked juvenile parkinsonism could be caused by a RAB39B mutation, and basal ganglia calcification may be a novel clinical feature of RAB39B-related parkinsonism. (PMID:27943471)
• we report on two novel RAB39B frameshift variants associated with X-linked Parkinsonism associated with Intellectual Disability and we also describe, for the first time, a somatic mosaicism in a patient carrying RAB39B mutation (PMID:28851564)
• penetrance for autism spectrum disorder is high among males but more variable among females with RAB39B mutations; a critical role for this gene in brain development and function is demonstrated (PMID:29152164)
• RAB39B is redistributed in dementia with Lewy bodies and is sequestered within abeta plaques and Lewy bodies. (PMID:32762091)
• Clinical characterization of a novel RAB39B nonstop mutation in a family with ASD and severe ID causing RAB39B downregulation and study of a Rab39b knock down mouse model. (PMID:34761259)
• Deficiency of RAB39B Activates ER Stress-Induced Pro-apoptotic Pathway and Causes Mitochondrial Dysfunction and Oxidative Stress in Dopaminergic Neurons by Impairing Autophagy and Upregulating alpha-Synuclein. (PMID:36715921)
• Novel RAB39B Mutation Causes Parkinsonism in Males with Developmental Disorder. (PMID:38293822)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rab39ba	ENSDARG00000019312
danio_rerio	rab39bb	ENSDARG00000036501
mus_musculus	Rab39b	ENSMUSG00000031202

Paralogs (68): RAB27B (ENSG00000041353), RAB27A (ENSG00000069974), RAB7A (ENSG00000075785), RABL2B (ENSG00000079974), RAB21 (ENSG00000080371), RAB10 (ENSG00000084733), RAB18 (ENSG00000099246), RAB36 (ENSG00000100228), IFT27 (ENSG00000100360), RAB40AL (ENSG00000102128), RAB11A (ENSG00000103769), RAB2A (ENSG00000104388), RAB3D (ENSG00000105514), RAB3A (ENSG00000105649), RAB5C (ENSG00000108774), RAB34 (ENSG00000109113), RAB5B (ENSG00000111540), RAB35 (ENSG00000111737), RAB23 (ENSG00000112210), DNAJC27 (ENSG00000115137), RAB29 (ENSG00000117280), RAB32 (ENSG00000118508), RAB14 (ENSG00000119396), RAB9B (ENSG00000123570), RAB9A (ENSG00000123595), RAB38 (ENSG00000123892), RAB22A (ENSG00000124209), RAB17 (ENSG00000124839), RAB2B (ENSG00000129472), RAB25 (ENSG00000132698), RAB33A (ENSG00000134594), RAB30 (ENSG00000137502), RAB1A (ENSG00000138069), RAB20 (ENSG00000139832), RAB15 (ENSG00000139998), RAB40B (ENSG00000141542), RAB13 (ENSG00000143545), RABL2A (ENSG00000144134), RAB5A (ENSG00000144566), RAB19 (ENSG00000146955)

Protein

Protein identifiers

Ras-related protein Rab-39B — Q96DA2 (reviewed: Q96DA2)

All UniProt accessions (1): Q96DA2

UniProt curated annotations — full annotation on UniProt →

Function. The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. RAB39B is involved in autophagy and may function in autophagosome formation. Binds downstream effector PICK1 to ensure selectively GRIA2 exit from the endoplasmic reticulum to the Golgi and to regulate AMPAR composition at the post-synapses and thus synaptic transmission. May regulate the homeostasis of SNCA/alpha-synuclein.

Subunit / interactions. Interacts (GDP-bound) with C9orf72; C9orf72 in complex with SMCR8 acts as a GEF for RAB39B. Interacts (in GTP-bound form) with PICK1 (via PDZ domain); a PICK1 homodimer may allow simultaneous association of RAB39B and GRIA2 to PICK1 which is involved in GRIA2 trafficking. Interacts with isoform c of RASSF1; the interaction is strong. Interacts with isoform a of RASSF1; the interaction is weak. Interacts with the DLG4/PSD-95. Interacts (GTP-bound) with HOPS complex components VPS39 and VPS41.

Subcellular location. Cell membrane. Cytoplasmic vesicle membrane. Golgi apparatus. Cytoplasmic vesicle. Autophagosome membrane. Autolysosome membrane.

Tissue specificity. Highly expressed in the brain.

Disease relevance. Intellectual developmental disorder, X-linked 72 (XLID72) [MIM:300271] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked forms, while syndromic forms present with associated physical, neurological and/or psychiatric manifestations. XLID72 patients can manifest autism spectrum disorder, seizures and macrocephaly as additional features. The disease is caused by variants affecting the gene represented in this entry. Waisman syndrome (WSMN) [MIM:311510] A neurologic disorder characterized by delayed psychomotor development, intellectual disability, and early-onset Parkinson disease. The disease is caused by variants affecting the gene represented in this entry. Its association with Parkinson disease is however unclear. According to a number of studies, variations affecting this gene are not a frequent cause of Parkinson disease, suggesting that RAB39B does not play a major role in Parkinson disease etiology.

Activity regulation. Regulated by guanine nucleotide exchange factors (GEFs) including C9orf72-SMCR8 complex, which promote the exchange of bound GDP for free GTP. Regulated by GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity. Inhibited by GDP dissociation inhibitors (GDIs).

Domain organisation. Switch I, switch II and the interswitch regions are characteristic of Rab GTPases and mediate the interactions with Rab downstream effectors. The switch regions undergo conformational changes upon nucleotide binding which drive interaction with specific sets of effector proteins, with most effectors only binding to GTP-bound Rab.

Similarity. Belongs to the small GTPase superfamily. Rab family.

RefSeq proteins (1): NP_741995* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001806	Small_GTPase	Family
IPR005225	Small_GTP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR041818	Rab39	Family
IPR050209	Rab_GTPases_membrane_traffic	Family

Pfam: PF00071

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (46 total): binding site 16, strand 8, helix 8, sequence variant 3, region of interest 2, modified residue 2, lipid moiety-binding region 2, mutagenesis site 2, chain 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6S5F	X-RAY DIFFRACTION	1.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96DA2-F1	88.67	0.74

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (16): 40; 40; 64; 67; 123; 124; 126; 154; 155; 17; 20; 21 …

Post-translational modifications (4): 201, 213, 211, 213

Mutagenesis-validated functional residues (2):

Position	Phenotype
22	dominant negative mutant.
68	constitutively active mutant locked in the active gtp-bound form.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-8873719	RAB geranylgeranylation
R-HSA-8876198	RAB GEFs exchange GTP for GDP on RABs

MSigDB gene sets: 161 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GOBP_REGULATION_OF_AUTOPHAGY, GOCC_VACUOLAR_MEMBRANE, GAUSSMANN_MLL_AF4_FUSION_TARGETS_G_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOCC_NEURON_PROJECTION, GOBP_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOCC_AUTOPHAGOSOME, GOCC_AUTOPHAGOSOME_MEMBRANE, GARY_CD5_TARGETS_UP, GOMF_GTPASE_ACTIVITY, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_ACID_ANHYDRIDES

GO Biological Process (6): autophagy (GO:0006914), regulation of autophagy (GO:0010506), protein transport (GO:0015031), vesicle-mediated transport (GO:0016192), Rab protein signal transduction (GO:0032482), synapse organization (GO:0050808)

GO Molecular Function (8): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), myosin V binding (GO:0031489), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (10): autophagosome membrane (GO:0000421), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), cytoplasmic vesicle membrane (GO:0030659), vesicle (GO:0031982), neuron projection (GO:0043005), autolysosome membrane (GO:0120281), lysosome (GO:0005764), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Post-translational protein modification	1
Rab regulation of trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	2
cytoplasm	2
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
autophagy	1
regulation of catabolic process	1
intracellular protein localization	1
establishment of protein localization	1
cellular process	1
small GTPase-mediated signal transduction	1
cell junction organization	1
ribonucleoside triphosphate phosphatase activity	1
GTPase activity	1
molecular function regulator activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
myosin binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
vacuolar membrane	1
autophagosome	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
vesicle membrane	1
cytoplasmic vesicle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
lysosomal membrane	1
autolysosome	1
lytic vacuole	1
cellular anatomical structure	1
intracellular vesicle	1

Protein interactions and networks

STRING

1136 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAB39B	GDI1	P31150	874
RAB39B	SMCR8	Q8TEV9	729
RAB39B	WDR41	Q9HAD4	723
RAB39B	VPS35	Q96QK1	636
RAB39B	DNAJC6	O75061	633
RAB39B	TMEM230	Q96A57	622
RAB39B	DNAJC13	O75165	612
RAB39B	ATP13A2	Q9NQ11	606
RAB39B	VPS13C	Q709C8	605
RAB39B	CHCHD2	Q9Y6H1	598
RAB39B	PTRHD1	Q6GMV3	592
RAB39B	PLA2G6	O60733	588
RAB39B	FBXO7	Q9Y3I1	582
RAB39B	MADD	Q8WXG6	581
RAB39B	SYNJ1	O43426	581

IntAct

58 interactions, top by confidence:

A	B	Type	Score
C9orf72	SMCR8	psi-mi:“MI:2252”(guanine nucleotide exchange factor reaction)	0.850
KPNA2	NUP153	psi-mi:“MI:0914”(association)	0.790
RAB39B	GOLGA2	psi-mi:“MI:0915”(physical association)	0.670
RAB39B	RUFY1	psi-mi:“MI:0915”(physical association)	0.670
GOLGA2	RAB39B	psi-mi:“MI:0915”(physical association)	0.670
RUFY1	RAB39B	psi-mi:“MI:0915”(physical association)	0.670
TOMM22	XRCC3	psi-mi:“MI:0914”(association)	0.640
TNFSF8	TOR1B	psi-mi:“MI:0914”(association)	0.640
VPS26C	RAB39B	psi-mi:“MI:0915”(physical association)	0.560
SLC15A1	METTL15	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
ALPI	ALPP	psi-mi:“MI:0914”(association)	0.530
RAB39B	CBL	psi-mi:“MI:0914”(association)	0.530
LRP1	NME4	psi-mi:“MI:0914”(association)	0.530
SLC39A9	B4GALT5	psi-mi:“MI:0914”(association)	0.530
ZDHHC17	RAB39B	psi-mi:“MI:0915”(physical association)	0.510
RAB39B	BECN1	psi-mi:“MI:0915”(physical association)	0.400
RAB39B	SMCR8	psi-mi:“MI:0915”(physical association)	0.400
RAB39B	SQSTM1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (75): RAB39B (Two-hybrid), RAB39B (Two-hybrid), RAB39B (Two-hybrid), RAB39B (Affinity Capture-Western), RAB39B (Affinity Capture-MS), RAB39B (Affinity Capture-MS), GOLGA2 (Two-hybrid), WHAMM (Affinity Capture-MS), CLEC16A (Affinity Capture-MS), TRIM4 (Affinity Capture-MS), CBL (Affinity Capture-MS), RAB39B (Affinity Capture-MS), TRIP6 (Affinity Capture-MS), RAB39B (Affinity Capture-MS), RAB39B (Affinity Capture-MS)

ESM2 similar proteins: C8VQY7, H9BW96, O14966, O49513, O76742, O97572, P09527, P17610, P18067, P25766, P28185, P36411, P36864, P51149, P51150, P57729, P62490, P62491, P62492, P62493, P62494, P93267, Q06AU5, Q17QU4, Q1PEX3, Q2TA29, Q39572, Q3T0F5, Q40194, Q40195, Q40523, Q40723, Q41640, Q52NJ1, Q54QR3, Q5R7A4, Q5R9M7, Q5R9Y4, Q5ZJN2, Q63481

Diamond homologs: A4IHM6, F1PTE3, F4KFD8, O13876, O23657, O49841, P35286, P51153, P51157, P51158, P51159, Q14964, Q17QU4, Q18969, Q32LJ6, Q3SWY9, Q58DS5, Q5HYI8, Q5KTJ6, Q5RFI2, Q5UQ27, Q5ZKR4, Q6GPS4, Q6TNS7, Q7T3A4, Q7Z6P3, Q8BHC1, Q8BHD0, Q8N4Z0, Q948K8, Q96DA2, Q99KL7, Q9C5J9, Q9D4V7, Q9DD03, Q9SJ11, A4FV54, O04486, O18333, O23561

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RAB39B	“up-regulates activity”	PICK1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

114 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	5
Uncertain significance	55
Likely benign	12
Benign	12

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
10542	NM_171998.4(RAB39B):c.215+1G>A	Pathogenic
10543	NM_171998.4(RAB39B):c.21C>A (p.Tyr7Ter)	Pathogenic
156532	NM_171998.4(RAB39B):c.503C>A (p.Thr168Lys)	Pathogenic
218362	NM_171998.4(RAB39B):c.574G>A (p.Gly192Arg)	Pathogenic
2809751	NM_171998.4(RAB39B):c.188G>A (p.Trp63Ter)	Pathogenic
436462	NM_171998.4(RAB39B):c.559G>T (p.Glu187Ter)	Pathogenic
1343162	NM_171998.4(RAB39B):c.559del (p.Glu187fs)	Likely pathogenic
1691598	NM_171998.4(RAB39B):c.137dup (p.Ser47fs)	Likely pathogenic
3381756	NM_171998.4(RAB39B):c.426TGC[1] (p.Ala144del)	Likely pathogenic
633549	NM_171998.4(RAB39B):c.189G>T (p.Trp63Cys)	Likely pathogenic
816418	GRCh37/hg19 Xq28(chrX:154418280-154565718)x3	Likely pathogenic

SpliceAI

369 predictions. Top by Δscore:

Variant	Effect	Δscore
X:155262443:A:T	acceptor_gain	0.9900
X:155263905:T:A	donor_gain	0.9900
X:155264086:TG:T	donor_gain	0.9900
X:155264124:T:TA	donor_gain	0.9900
X:155264068:TCCCA:T	donor_loss	0.9800
X:155264069:CCCAC:C	donor_loss	0.9800
X:155264070:CCA:C	donor_loss	0.9800
X:155264072:A:C	donor_loss	0.9800
X:155264073:C:CT	donor_loss	0.9800
X:155263886:C:A	donor_gain	0.9700
X:155264228:TGCCC:T	donor_gain	0.9700
X:155262442:C:CT	acceptor_gain	0.9600
X:155264084:CTTG:C	donor_gain	0.9600
X:155264195:G:GT	donor_gain	0.9600
X:155264233:A:AC	donor_gain	0.9600
X:155264234:C:CC	donor_gain	0.9600
X:155264229:G:A	donor_gain	0.9500
X:155262450:T:C	acceptor_gain	0.9400
X:155264081:T:TA	donor_gain	0.9400
X:155263885:T:TA	donor_gain	0.9300
X:155264069:C:CA	donor_gain	0.9300
X:155264087:G:T	donor_gain	0.9300
X:155261230:C:CC	acceptor_gain	0.9200
X:155261227:GATCT:G	acceptor_loss	0.9100
X:155261229:TCTAA:T	acceptor_loss	0.9100
X:155261231:T:G	acceptor_loss	0.9100
X:155264227:TTGCC:T	donor_gain	0.9100
X:155264105:T:C	donor_gain	0.8900
X:155264266:TGG:T	donor_gain	0.8900
X:155261232:A:C	acceptor_loss	0.8800

AlphaMissense

1386 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:155264076:G:C	F71L	1.000
X:155264076:G:T	F71L	1.000
X:155264078:A:G	F71L	1.000
X:155264098:T:A	D64V	1.000
X:155264098:T:G	D64A	1.000
X:155264099:C:G	D64H	1.000
X:155264102:A:G	W63R	1.000
X:155264102:A:T	W63R	1.000
X:155264245:C:T	G15E	1.000
X:155261073:C:A	K124N	0.999
X:155261073:C:G	K124N	0.999
X:155261075:T:C	K124E	0.999
X:155261080:C:T	G122D	0.999
X:155261136:C:A	W103C	0.999
X:155261136:C:G	W103C	0.999
X:155261138:A:G	W103R	0.999
X:155261138:A:T	W103R	0.999
X:155261178:A:C	F89L	0.999
X:155261178:A:T	F89L	0.999
X:155261180:A:G	F89L	0.999
X:155261194:C:T	G84D	0.999
X:155264078:A:T	F71I	0.999
X:155264089:C:T	G67D	0.999
X:155264090:C:A	G67C	0.999
X:155264090:C:G	G67R	0.999
X:155264097:A:C	D64E	0.999
X:155264097:A:T	D64E	0.999
X:155264098:T:C	D64G	0.999
X:155264099:C:A	D64Y	0.999
X:155264100:C:A	W63C	0.999

dbSNP variants (sampled 300 via entrez): RS1000749670 (X:155266355 T>C,G), RS1000893915 (X:155258614 G>A), RS1000965534 (X:155258134 G>A), RS1003662716 (X:155262958 C>A), RS1004225121 (X:155261926 G>A), RS1004416790 (X:155262485 A>G), RS1008244571 (X:155264372 G>A,C), RS1008339567 (X:155263955 C>G,T), RS1010652318 (X:155261708 G>C), RS1011663311 (X:155264516 T>A,C), RS1012344584 (X:155259200 A>G,T), RS1012704915 (X:155258629 T>G), RS1013481000 (X:155265393 G>A), RS1015242961 (X:155265039 A>G), RS1016921448 (X:155262514 C>A)

Disease associations

OMIM: gene MIM:300774 | disease phenotypes: MIM:300271, MIM:311510

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, X-linked 72	Definitive	X-linked
early-onset parkinsonism-intellectual disability syndrome	Strong	X-linked
non-syndromic X-linked intellectual disability	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
early-onset parkinsonism-intellectual disability syndrome	Definitive	XL

Mondo (4): intellectual disability, X-linked 72 (MONDO:0010289), early-onset parkinsonism-intellectual disability syndrome (MONDO:0010709), neurodevelopmental disorder (MONDO:0700092), non-syndromic X-linked intellectual disability (MONDO:0019181)

Orphanet (2): X-linked non-syndromic intellectual disability (Orphanet:777), Early-onset parkinsonism-intellectual disability syndrome (Orphanet:2379)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000256	Macrocephaly
HP:0000268	Dolichocephaly
HP:0000276	Long face
HP:0000486	Strabismus
HP:0000726	Dementia
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000752	Hyperactivity
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001256	Mild intellectual disability
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001300	Parkinsonism
HP:0001355	Megalencephaly
HP:0001419	X-linked recessive inheritance
HP:0002007	Frontal bossing
HP:0002063	Rigidity
HP:0002067	Bradykinesia
HP:0002167	Abnormal speech pattern
HP:0002172	Postural instability
HP:0002322	Resting tremor
HP:0002362	Shuffling gait
HP:0002396	Cogwheel rigidity
HP:0002465	Poor speech
HP:0002548	Parkinsonism with favorable response to dopaminergic medication
HP:0003596	Middle age onset
HP:0004322	Short stature
HP:0011462	Young adult onset
HP:0100022	Abnormality of movement

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
C564547	Mental Retardation, X-Linked 72 (supp.)
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)
C537179	Parkinsonism, early onset with mental retardation (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

47 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression, increases expression	3
Valproic Acid	decreases methylation, increases expression	3
bisphenol A	affects expression, affects binding, increases reaction	2
Nickel	increases expression	2
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
methylparaben	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	decreases methylation	1
stearic acid	increases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
NSC 689534	affects binding, increases expression	1
Sunitinib	increases expression	1
Glyphosate	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Amiodarone	increases expression	1
Benzo(a)pyrene	affects methylation	1
Camptothecin	increases expression	1
Capsaicin	increases expression	1
Copper	affects binding, increases expression	1

Cellosaurus cell lines

9 cell lines: 4 cancer cell line, 3 induced pluripotent stem cell, 2 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A5GT	ZZUi027-A	Induced pluripotent stem cell	Male
CVCL_D1U5	Abcam U-87MG RAB39B KO	Cancer cell line	Male
CVCL_E2IA	HAP1 RAB39B (-) 1	Cancer cell line	Male
CVCL_E2IB	HAP1 RAB39B (-) 2	Cancer cell line	Male
CVCL_E2IC	HAP1 RAB39B (-) 3	Cancer cell line	Male
CVCL_E5EF	KOLF2.1J RAB39B T168K SNV/Y	Induced pluripotent stem cell	Male
CVCL_LE98	ZZUi005-A	Induced pluripotent stem cell	Male
CVCL_VE95	SCSe001-A-1	Embryonic stem cell	Male
CVCL_VE96	SCSe001-A-2	Embryonic stem cell	Male

Clinical trials (associated diseases)

202 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice