RAB33B

Summary

RAB33B (RAB33B, member RAS oncogene family, HGNC:16075) is a protein-coding gene on chromosome 4q31.1, encoding Ras-related protein Rab-33B (Q9H082). The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.

This gene encodes a small GTP-binding protein of the Rab GTPase family, whose members function in vesicle transport during protein secretion and endocytosis. Rab GTPases are active, membrane-associated proteins that recruit effector proteins in the GTP-bound state and inactive cytosolic proteins when in a GDP-bound state. The protein encoded by this gene is ubiquitously expressed and has been implicated in Golgi to endoplasmic reticulum cycling of Golgi enzymes. In addition, this protein regulates Golgi homeostasis and coordinates intra-Golgi retrograde trafficking. Allelic variants in this gene have been associated with Dyggve-Melchior-Clausen syndrome and Smith-McCort dysplasia 2, which are autosomal recessive spondyloepimetaphyseal dysplasias characterized by skeletal abnormalities.

Source: NCBI Gene 83452 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Smith-McCort dysplasia 2 (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 129 total — 8 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 29
• MANE Select transcript: NM_031296

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16075
Approved symbol	RAB33B
Name	RAB33B, member RAS oncogene family
Location	4q31.1
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP434G099
Ensembl gene	ENSG00000172007
Ensembl biotype	protein_coding
OMIM	605950
Entrez	83452

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000305626, ENST00000507271, ENST00000652268, ENST00000873886, ENST00000930373

RefSeq mRNA: 1 — MANE Select: NM_031296 NM_031296

CCDS: CCDS3747

Canonical transcript exons

ENST00000305626 — 2 exons

Exon	Start	End
ENSE00001147293	139472686	139476609
ENSE00001147304	139454121	139454444

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 89.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.2687 / max 116.0601, expressed in 1750 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
49751	7.4870	1726
49750	0.9975	657
49752	0.7842	444

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	89.26	gold quality
saphenous vein	UBERON:0007318	87.56	gold quality
vein	UBERON:0001638	86.74	gold quality
urethra	UBERON:0000057	86.38	gold quality
CA1 field of hippocampus	UBERON:0003881	86.10	gold quality
subthalamic nucleus	UBERON:0001906	85.91	gold quality
synovial joint	UBERON:0002217	85.66	gold quality
blood vessel layer	UBERON:0004797	85.44	gold quality
lateral nuclear group of thalamus	UBERON:0002736	85.27	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	85.14	silver quality
inferior olivary complex	UBERON:0002127	84.96	gold quality
superficial temporal artery	UBERON:0001614	84.90	gold quality
dorsal plus ventral thalamus	UBERON:0001897	84.42	gold quality
vena cava	UBERON:0004087	84.34	silver quality
pons	UBERON:0000988	84.27	gold quality
choroid plexus epithelium	UBERON:0003911	84.13	gold quality
endothelial cell	CL:0000115	83.71	gold quality
right lobe of liver	UBERON:0001114	83.35	gold quality
dorsal root ganglion	UBERON:0000044	83.34	gold quality
substantia nigra pars reticulata	UBERON:0001966	83.04	gold quality
inferior vagus X ganglion	UBERON:0005363	83.00	gold quality
medulla oblongata	UBERON:0001896	82.99	gold quality
liver	UBERON:0002107	82.89	gold quality
bone marrow	UBERON:0002371	82.75	gold quality
hair follicle	UBERON:0002073	82.65	silver quality
trabecular bone tissue	UBERON:0002483	82.48	gold quality
pericardium	UBERON:0002407	82.47	gold quality
trigeminal ganglion	UBERON:0001675	82.17	gold quality
amniotic fluid	UBERON:0000173	82.15	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.89	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.72
E-ENAD-17	no	145.08
E-GEOD-83139	no	3.26

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

173 targeting RAB33B, 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-5011-5P	100.00	83.46	5820
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3065-5P	99.97	71.56	3281

Literature-anchored findings (GeneRIF, showing 12)

• Rab33 modulates autophagosome formation through interaction with Atg16L (PMID:18448665)
• A second autosomal recessive locus for Dyggve-Melchior-Clausen syndrome exists on 4q31.1 and that Rab protein-encoding gene, RAB33B, is the likely disease gene in that locus. (PMID:22652534)
• Ric1-Rgp1 complex is a guanine nucleotide exchange factor for the late Golgi Rab6A GTPase and an effector of the medial Golgi Rab33B GTPase. (PMID:23091056)
• Analysis of hepatitis B virus capsid maturation steps revealed that Rab33B and Atg5/12/16L1 are required for proper particle assembly and/or stability. (PMID:25439980)
• Arg-24 of Atg16L1 is crucial for its interaction with Atg5 which has implications in the binding of the dimeric complex to Rab33B (PMID:26975471)
• Rab33b, OATL1 and Myo6 have roles in nanoparticle trafficking in HeLa cells (PMID:27374232)
• Here we present three SMC patients with four novel pathogenic variants in RAB33B, including homozygosity for c.211C>T (p.R71*), homozygosity for c.365T>C (p.F122S), and compound heterozygosity for c.48delCGGGGCAG (p.G17Vfs*58) and c.490C>T (p.Q164*). (PMID:28127940)
• Together, these results indicate that Rab33B is an important player in intracellular hepatitis B virus trafficking events, guiding core transport to nucleocapsid assembly sites and/or nucleocapsid transport to budding sites. (PMID:28635671)
• This review focus is on the current knowledge of the participation of Rab33b and its interacting partners in membrane trafficking and macroautophagy, and speculate on how its function, and dysfunction, may contribute to human disease.[review] (PMID:31408960)
• RAB33B recruits the ATG16L1 complex to the phagophore via a noncanonical RAB binding protein. (PMID:32960676)
• Seven patients with Smith-McCort dysplasia 2: Four novel nonsense variants in RAB33B and follow-up findings. (PMID:34000439)
• RAB33B and PCNT variants in two Pakistani families with skeletal dysplasia and short stature. (PMID:34284742)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rab33ba	ENSDARG00000052290
mus_musculus	Rab33b	ENSMUSG00000027739
rattus_norvegicus	Rab33b	ENSRNOG00000013035

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-33B — Q9H082 (reviewed: Q9H082)

All UniProt accessions (2): Q9H082, A0A494C0Z5

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. RAB33B acts, in coordination with RAB6A, to regulate intra-Golgi retrograde trafficking. Participates in autophagosome formation by recruiting the ATG12-ATG5-ATG16L1 complex to phagophores, probably in a nucleotide-independent manner.

Subunit / interactions. Interacts (GTP- and GDP-bound forms) with ATG16L1; the complex consists of a tetramer where two RAB33B molecules bind independently one molecule of the ATG16L1 homodimer; the interaction promotes ATG12-ATG5-ATG16L1 complex recruitment to phagophores. Interacts with ATG16L2; however interaction is approximately hundred times lower than for ATG16L1. Interacts with RIC1 (via C-terminus domain); the interaction is direct with a preference for RAB33B-GTP. Interacts with RGP1.

Subcellular location. Golgi apparatus membrane. Golgi apparatus. cis-Golgi network. Preautophagosomal structure membrane.

Post-translational modifications. Prenylated.

Disease relevance. Smith-McCort dysplasia 2 (SMC2) [MIM:615222] A rare autosomal recessive osteochondrodysplasia with skeletal features identical to those of Dyggve-Melchior-Clausen syndrome, but with normal intelligence and no microcephaly. It is characterized by short limbs and trunk with barrel-shaped chest. The radiographic phenotype includes platyspondyly, generalized abnormalities of the epiphyses and metaphyses, and a distinctive lacy appearance of the iliac crest. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP. Regulated by GTPase activating proteins (GAPs) such as SGSM2 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. Although most effectors only bind GTP-bound Rab, ATG16L1 effector binds both GTP- and GDP-bound RAB33B.

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

RefSeq proteins (1): NP_112586* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001806	Small_GTPase	Family
IPR005225	Small_GTP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR041822	Rab33A/B	Family

Pfam: PF00071

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (46 total): binding site 17, strand 8, helix 8, mutagenesis site 4, region of interest 2, lipid moiety-binding region 2, sequence variant 2, chain 1, modified residue 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6Y09	X-RAY DIFFRACTION	2.4
6ZAY	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H082-F1	81.55	0.60

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 (17): 62; 65; 65; 88; 91; 148; 149; 151; 179; 180; 43; 44 …

Post-translational modifications (3): 229, 227, 229

Mutagenesis-validated functional residues (4):

Position	Phenotype
35	loss of interaction with atg16l1. no change in prenylation activity. loss of interaction with atg12-atg5-atg16l1 complex
66	decreased binding affinity by 273-fold with atg16l1. no change in prenylation activity. loss of interaction with atg16l1
85	loss of interaction with atg16l1. no change in prenylation activity. loss of interaction with atg12-atg5-atg16l1 complex
95	decreased binding affinity by 179-fold with atg16l1. no change in prenylation activity. loss of interaction with atg16l1

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6811438	Intra-Golgi traffic
R-HSA-8854214	TBC/RABGAPs
R-HSA-8873719	RAB geranylgeranylation

MSigDB gene sets: 301 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_REGULATION_OF_GOLGI_ORGANIZATION, GOBP_VACUOLE_ORGANIZATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_GROWTH, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_EXOCYTOSIS, REACTOME_MEMBRANE_TRAFFICKING, GOBP_INTRA_GOLGI_VESICLE_MEDIATED_TRANSPORT, GOBP_MACROAUTOPHAGY, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_EXOCYTOSIS, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT

GO Biological Process (12): autophagosome assembly (GO:0000045), intra-Golgi vesicle-mediated transport (GO:0006891), protein transport (GO:0015031), regulation of exocytosis (GO:0017157), Rab protein signal transduction (GO:0032482), protein localization to Golgi apparatus (GO:0034067), protein localization to phagophore assembly site (GO:0034497), skeletal system morphogenesis (GO:0048705), regulation of Golgi organization (GO:1903358), negative regulation of constitutive secretory pathway (GO:1903434), regulation of retrograde vesicle-mediated transport, Golgi to ER (GO:2000156), autophagy (GO:0006914)

GO Molecular Function (6): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (8): Golgi membrane (GO:0000139), endosome (GO:0005768), Golgi apparatus (GO:0005794), Golgi lumen (GO:0005796), phagophore assembly site membrane (GO:0034045), presynapse (GO:0098793), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Intra-Golgi and retrograde Golgi-to-ER traffic	1
Rab regulation of trafficking	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular protein localization	2
regulation of vesicle-mediated transport	2
Golgi apparatus	2
endomembrane system	2
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
Golgi vesicle transport	1
transport	1
establishment of protein localization	1
exocytosis	1
regulation of secretion by cell	1
small GTPase-mediated signal transduction	1
protein localization to organelle	1
autophagosome assembly	1
skeletal system development	1
animal organ morphogenesis	1
Golgi organization	1
regulation of organelle organization	1
constitutive secretory pathway	1
negative regulation of exocytosis	1
regulation of constitutive secretory pathway	1
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
ribonucleoside triphosphate phosphatase activity	1
GTPase activity	1
molecular function regulator activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1

Protein interactions and networks

STRING

1813 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAB33B	ATG16L1	Q676U5	992
RAB33B	ATG5	Q9H1Y0	859
RAB33B	RIC1	Q4ADV7	799
RAB33B	TBC1D25	Q3MII6	770
RAB33B	ATG12	O94817	714
RAB33B	GOLGA2	Q08379	700
RAB33B	ARF3	P16587	694
RAB33B	MAPK1IP1L	Q8NDC0	547
RAB33B	SGSM2	O43147	539
RAB33B	TBC1D14	Q9P2M4	532
RAB33B	DYM	Q7RTS9	507
RAB33B	TBC1D19	Q8N5T2	497
RAB33B	TBC1D20	Q96BZ9	476
RAB33B	DENND11	A4D1U4	469
RAB33B	RAB26	Q9ULW5	459

IntAct

43 interactions, top by confidence:

A	B	Type	Score
ATG16L1	RAB33B	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
RAB33B		psi-mi:“MI:0915”(physical association)	0.600
RAB33B		psi-mi:“MI:0407”(direct interaction)	0.600
RAB33B	RIC1	psi-mi:“MI:0914”(association)	0.590
RIC1	RAB33B	psi-mi:“MI:0407”(direct interaction)	0.590
RAB33B	RIC1	psi-mi:“MI:0915”(physical association)	0.590
RAB33B	SIAH1	psi-mi:“MI:0915”(physical association)	0.560
SIAH1	RAB33B	psi-mi:“MI:0915”(physical association)	0.560
RUFY2	RAB33B	psi-mi:“MI:0915”(physical association)	0.560
	RAB33B	psi-mi:“MI:0915”(physical association)	0.560
RAB3A	RAB3B	psi-mi:“MI:0914”(association)	0.530
RAB39B	CBL	psi-mi:“MI:0914”(association)	0.530
RAB6B	RAB6A	psi-mi:“MI:0914”(association)	0.530
RAB3A	CHM	psi-mi:“MI:0914”(association)	0.530
RAB1B	CHM	psi-mi:“MI:0914”(association)	0.530
RAB10	RAB33B	psi-mi:“MI:0915”(physical association)	0.400
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
CD177	MYO1G	psi-mi:“MI:0914”(association)	0.350
GABARAPL1		psi-mi:“MI:0914”(association)	0.350
	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
RAB33A	RAB19	psi-mi:“MI:0914”(association)	0.350

BioGRID (80): RAB33B (Affinity Capture-MS), RAB33B (Affinity Capture-MS), RAB33B (Affinity Capture-MS), RAB33B (Affinity Capture-MS), RAB33B (Affinity Capture-MS), RAB33B (Affinity Capture-MS), RAB33B (Affinity Capture-MS), RAB33B (Affinity Capture-MS), ATG5 (Reconstituted Complex), ATG16L1 (Reconstituted Complex), RAB33B (Reconstituted Complex), RAB33B (Reconstituted Complex), ATG16L1 (Reconstituted Complex), ATG16L2 (Reconstituted Complex), ATG16L2 (Two-hybrid)

ESM2 similar proteins: A5D7F5, C8VQY7, G4MYS1, H9BW96, I1RMF2, O04157, O24461, O76742, O94655, O97572, P09527, P18067, P24408, P31022, P36411, P36864, P51149, P51150, P51151, P91580, P93267, P97950, Q14088, Q39573, Q3T0F5, Q40787, Q41640, Q43463, Q54QR3, Q5M7D1, Q5R615, Q5R9Y4, Q5RDE5, Q5ZHV1, Q6IMK3, Q6IML7, Q6IMM1, Q7ZYF1, Q8CFP6, Q948K8

Diamond homologs: A4FV54, A6ZSH6, B3LPD8, B5VQB6, F1PTE3, O04157, O04486, O35963, O49513, O76173, P01123, P17610, P22125, P22127, P22128, P24409, P31022, P31584, P34140, P34143, P35280, P35282, P35286, P35289, P36412, P40392, P48559, P51153, P51156, P51996, P55258, P55745, P59190, P61006, P61007, P61026, P61027, P61028, P62820, P62821

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RAB33B	up-regulates	ATG16L1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 30 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RAB geranylgeranylation	12	76.9×	1e-18
RAB GEFs exchange GTP for GDP on RABs	9	41.4×	3e-11

GO biological processes:

GO term	Partners	Fold	FDR
antigen processing and presentation	5	117.0×	7e-08
autophagosome assembly	7	52.4×	1e-08
intracellular protein transport	7	15.1×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	2
Uncertain significance	74
Likely benign	30
Benign	6

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1048093	NM_031296.3(RAB33B):c.400C>T (p.Gln134Ter)	Pathogenic
1098420	NM_031296.3(RAB33B):c.253C>T (p.Gln85Ter)	Pathogenic
1098421	NM_031296.3(RAB33B):c.144C>A (p.Cys48Ter)	Pathogenic
1098422	NM_031296.3(RAB33B):c.280C>T (p.Arg94Ter)	Pathogenic
3655222	NM_031296.3(RAB33B):c.16G>T (p.Glu6Ter)	Pathogenic
425562	NM_031296.3(RAB33B):c.48_55del (p.Gly17fs)	Pathogenic
425563	NM_031296.3(RAB33B):c.490C>T (p.Gln164Ter)	Pathogenic
50231	NM_031296.3(RAB33B):c.444T>A (p.Asn148Lys)	Pathogenic
3655223	NM_031296.3(RAB33B):c.169dup (p.Arg57fs)	Likely pathogenic
50230	NM_031296.3(RAB33B):c.136A>C (p.Lys46Gln)	Likely pathogenic

SpliceAI

244 predictions. Top by Δscore:

Variant	Effect	Δscore
4:139454442:AAGGT:A	donor_loss	1.0000
4:139454443:AGG:A	donor_loss	1.0000
4:139454445:GTGA:G	donor_loss	1.0000
4:139454446:T:G	donor_loss	1.0000
4:139454445:G:GG	donor_gain	0.9900
4:139472678:A:AG	acceptor_gain	0.9900
4:139472679:T:G	acceptor_gain	0.9900
4:139472682:TTAG:T	acceptor_loss	0.9900
4:139472684:A:AG	acceptor_gain	0.9900
4:139472684:AGA:A	acceptor_loss	0.9900
4:139472685:G:GA	acceptor_gain	0.9900
4:139472685:GATCC:G	acceptor_gain	0.9900
4:139472682:TTAGA:T	acceptor_gain	0.9800
4:139472683:TAGA:T	acceptor_gain	0.9800
4:139472684:AGATC:A	acceptor_gain	0.9800
4:139472685:GAT:G	acceptor_gain	0.9800
4:139472685:GATC:G	acceptor_gain	0.9700
4:139472685:G:T	acceptor_gain	0.9600
4:139472681:TTTA:T	acceptor_gain	0.9500
4:139472685:GA:G	acceptor_gain	0.9500
4:139454443:AG:A	donor_gain	0.9400
4:139454444:GG:G	donor_gain	0.9400
4:139453919:TCCC:T	donor_gain	0.9300
4:139472680:TTTTA:T	acceptor_gain	0.9300
4:139453936:T:TA	donor_gain	0.8500
4:139453937:A:AA	donor_gain	0.8500
4:139454432:G:GT	donor_gain	0.8400
4:139454432:G:T	donor_gain	0.8300
4:139472750:GAAAT:G	donor_gain	0.8200
4:139453938:GACCG:G	donor_gain	0.8100

AlphaMissense

1529 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:139454313:G:C	G40R	1.000
4:139454314:G:A	G40D	1.000
4:139454314:G:T	G40V	1.000
4:139454329:G:A	G45D	1.000
4:139454331:A:C	K46Q	1.000
4:139454335:C:T	T47I	1.000
4:139454395:G:A	G67E	1.000
4:139472695:T:A	W87R	1.000
4:139472695:T:C	W87R	1.000
4:139472698:G:C	D88H	1.000
4:139472698:G:T	D88Y	1.000
4:139472699:A:C	D88A	1.000
4:139472699:A:G	D88G	1.000
4:139472699:A:T	D88V	1.000
4:139472700:C:A	D88E	1.000
4:139472700:C:G	D88E	1.000
4:139472719:T:C	F95L	1.000
4:139472721:C:A	F95L	1.000
4:139472721:C:G	F95L	1.000
4:139472761:G:C	A109P	1.000
4:139472881:A:G	K149E	1.000
4:139472882:A:T	K149I	1.000
4:139472883:A:C	K149N	1.000
4:139472883:A:T	K149N	1.000
4:139472936:C:A	A167D	1.000
4:139454313:G:T	G40C	0.999
4:139454328:G:C	G45R	0.999
4:139454329:G:T	G45V	0.999
4:139454331:A:G	K46E	0.999
4:139454332:A:T	K46M	0.999

dbSNP variants (sampled 300 via entrez): RS1000146386 (4:139476859 G>A), RS1000228789 (4:139441048 T>C), RS1000459281 (4:139457549 G>A), RS1000461776 (4:139446814 G>A), RS1000491259 (4:139447412 G>C), RS1000518509 (4:139476569 A>G), RS1000623831 (4:139474086 G>A), RS1000655804 (4:139453679 C>A), RS1000688558 (4:139453000 T>C), RS1000698716 (4:139467525 T>C), RS1000699544 (4:139459677 A>C), RS1000772408 (4:139445830 T>A,C), RS1000835577 (4:139442600 A>C,G), RS1000861252 (4:139470030 G>A,T), RS1000875905 (4:139448852 G>A)

Disease associations

OMIM: gene MIM:605950 | disease phenotypes: MIM:615222

GenCC curated gene-disease

Disease	Classification	Inheritance
Smith-McCort dysplasia 2	Strong	Autosomal recessive
Smith-McCort dysplasia	Supportive	Autosomal recessive

Mondo (2): Smith-McCort dysplasia 2 (MONDO:0014087), Smith-McCort dysplasia (MONDO:0015799)

Orphanet (0):

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000280	Coarse facial features
HP:0000303	Mandibular prognathia
HP:0000470	Short neck
HP:0000768	Pectus carinatum
HP:0000926	Platyspondyly
HP:0001249	Intellectual disability
HP:0001377	Limited elbow extension
HP:0001552	Barrel-shaped chest
HP:0001763	Pes planus
HP:0001783	Broad metatarsal
HP:0002857	Genu valgum
HP:0003025	Metaphyseal irregularity
HP:0003071	Flattened epiphysis
HP:0003180	Flat acetabular roof
HP:0003307	Hyperlordosis
HP:0003311	Hypoplasia of the odontoid process
HP:0003521	Disproportionate short-trunk short stature
HP:0004322	Short stature
HP:0004325	Decreased body weight
HP:0006009	Broad phalanx
HP:0006247	Enlarged interphalangeal joints
HP:0006429	Broad femoral neck
HP:0008812	Flattened femoral head
HP:0009803	Short phalanx of finger
HP:0010049	Short metacarpal
HP:0010743	Short metatarsal
HP:0011463	Childhood onset
HP:0012428	Prominent calcaneus

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C564589	Smith-McCort Dysplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression, affects expression	3
epigallocatechin gallate	increases expression, affects cotreatment	2
Valproic Acid	affects expression, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
methylparaben	increases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sodium arsenite	decreases expression, increases abundance	1
cobaltous chloride	decreases expression	1
nickel chloride	decreases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
CGP 52608	increases reaction, affects binding	1
K 7174	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
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
NSC668394	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	decreases expression, increases abundance	1
Cisplatin	increases expression	1
Coumestrol	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Methyl Methanesulfonate	increases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Dronabinol	decreases expression	1
Tretinoin	decreases expression	1
Urethane	increases expression	1
Vitamin E	decreases expression	1
Cyclosporine	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E2I8	HAP1 RAB33B (-) 1	Cancer cell line	Male
CVCL_E2I9	HAP1 RAB33B (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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