ARHGEF33

Summary

ARHGEF33 (Rho guanine nucleotide exchange factor 33, HGNC:37252) is a protein-coding gene on chromosome 2p22.1, encoding Rho guanine nucleotide exchange factor 33 (A8MVX0). May act as a guanine-nucleotide releasing factor.

Predicted to enable guanyl-nucleotide exchange factor activity.

Source: NCBI Gene 100271715 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 147 total — 2 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_001145451

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:37252
Approved symbol	ARHGEF33
Name	Rho guanine nucleotide exchange factor 33
Location	2p22.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000214694
Ensembl biotype	protein_coding
Entrez	100271715

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000398800, ENST00000409978, ENST00000411874, ENST00000430382, ENST00000433605, ENST00000483305, ENST00000486958, ENST00000488692, ENST00000698009, ENST00000850917

RefSeq mRNA: 2 — MANE Select: NM_001145451 NM_001145451, NM_001367623

CCDS: CCDS46263

Canonical transcript exons

ENST00000409978 — 18 exons

Exon	Start	End
ENSE00001534938	38954373	38954456
ENSE00001534941	38953162	38953245
ENSE00001534944	38950989	38951121
ENSE00001534946	38943901	38944030
ENSE00001534949	38937335	38937559
ENSE00001534956	38935775	38935834
ENSE00001534958	38931109	38931251
ENSE00001582795	38889875	38889986
ENSE00001583669	38928907	38929071
ENSE00001587927	38959841	38960648
ENSE00001588225	38973714	38975454
ENSE00001628279	38956899	38957047
ENSE00001643724	38958034	38958198
ENSE00003496496	38919363	38919472
ENSE00003558806	38921374	38921423
ENSE00003560982	38966006	38966145
ENSE00003571360	38895777	38895849
ENSE00003659838	38929709	38929830

Expression profiles

Bgee: expression breadth ubiquitous, 135 present calls, max score 88.21.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5067 / max 92.9922, expressed in 179 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
202163	0.3327	168
19844	0.0680	9
19845	0.0362	6
19842	0.0355	7
19843	0.0343	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	88.21	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.22	gold quality
cerebellum	UBERON:0002037	85.41	gold quality
cerebellar hemisphere	UBERON:0002245	85.40	gold quality
cerebellar cortex	UBERON:0002129	85.35	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.50	gold quality
right testis	UBERON:0004534	80.68	gold quality
testis	UBERON:0000473	80.66	gold quality
left testis	UBERON:0004533	80.65	gold quality
nucleus accumbens	UBERON:0001882	78.17	gold quality
brain	UBERON:0000955	76.00	gold quality
hypothalamus	UBERON:0001898	75.74	gold quality
pituitary gland	UBERON:0000007	75.71	gold quality
adenohypophysis	UBERON:0002196	75.67	gold quality
right frontal lobe	UBERON:0002810	75.43	gold quality
Ammon’s horn	UBERON:0001954	75.12	gold quality
amygdala	UBERON:0001876	75.07	gold quality
temporal lobe	UBERON:0001871	74.91	gold quality
caudate nucleus	UBERON:0001873	74.66	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	74.43	gold quality
Brodmann (1909) area 9	UBERON:0013540	74.21	gold quality
anterior cingulate cortex	UBERON:0009835	74.18	gold quality
cerebral cortex	UBERON:0000956	74.16	gold quality
frontal cortex	UBERON:0001870	74.12	gold quality
putamen	UBERON:0001874	73.70	gold quality
prefrontal cortex	UBERON:0000451	73.49	gold quality
corpus callosum	UBERON:0002336	73.12	gold quality
right uterine tube	UBERON:0001302	72.75	gold quality
superior frontal gyrus	UBERON:0002661	72.48	gold quality
left ovary	UBERON:0002119	72.44	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.83

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

116 targeting ARHGEF33, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-218-5P	99.93	72.22	2103

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Arhgef33	ENSMUSG00000054901
rattus_norvegicus	Arhgef33	ENSRNOG00000007061

Protein

Protein identifiers

Rho guanine nucleotide exchange factor 33 — A8MVX0 (reviewed: A8MVX0)

All UniProt accessions (4): A0A8V8TLC5, A0A8V8TLF0, A8MVX0, H7C1C9

UniProt curated annotations — full annotation on UniProt →

Function. May act as a guanine-nucleotide releasing factor.

Isoforms (2)

UniProt ID	Names	Canonical?
A8MVX0-1	1	yes
A8MVX0-2	2

RefSeq proteins (2): NP_001138923, NP_001354552 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR042849	ARHGEF33	Family

Pfam: PF00621

UniProt features (17 total): region of interest 7, compositionally biased region 5, chain 1, domain 1, modified residue 1, splice variant 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A8MVX0-F1	56.31	0.24

Functional residue map

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

Post-translational modifications (1): 757

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-193648	NRAGE signals death through JNK
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-162582	Signal Transduction
R-HSA-193704	p75 NTR receptor-mediated signalling
R-HSA-204998	Cell death signalling via NRAGE, NRIF and NADE
R-HSA-372790	Signaling by GPCR
R-HSA-388396	GPCR downstream signalling
R-HSA-73887	Death Receptor Signaling

MSigDB gene sets: 66 (showing top): REACTOME_NRAGE_SIGNALS_DEATH_THROUGH_JNK, GOMF_GUANYL_NUCLEOTIDE_EXCHANGE_FACTOR_ACTIVITY, GOMF_NUCLEOSIDE_TRIPHOSPHATASE_REGULATOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY, REACTOME_CELL_DEATH_SIGNALLING_VIA_NRAGE_NRIF_AND_NADE, chr2p22, REACTOME_DEATH_RECEPTOR_SIGNALING, MIR6867_5P, MIR520D_5P, MIR524_5P, LET_7A_3P, MIR98_3P, LET_7F_1_3P, LET_7B_3P, MIR4482_3P

GO Biological Process (0):

GO Molecular Function (1): guanyl-nucleotide exchange factor activity (GO:0005085)

GO Cellular Component (0):

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Signal Transduction	2
Cell death signalling via NRAGE, NRIF and NADE	1
GPCR downstream signalling	1
Death Receptor Signaling	1
p75 NTR receptor-mediated signalling	1
Signaling by GPCR	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
GTP binding	1
GDP binding	1
GTPase regulator activity	1

Protein interactions and networks

STRING

522 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARHGEF33	KRTAP2-1	Q9BYU5	545
ARHGEF33	OR8J1	Q8NGP2	521
ARHGEF33	ARHGEF10	O15013	512
ARHGEF33	KRTAP2-2	Q9BYT5	507
ARHGEF33	ARHGEF15	O94989	503
ARHGEF33	ANO4	Q32M45	485
ARHGEF33	ZNF592	Q92610	480
ARHGEF33	FGFBP3	Q8TAT2	476
ARHGEF33	ARHGEF38	Q9NXL2	470
ARHGEF33	ARHGEF11	O15085	462
ARHGEF33	PLEKHG7	Q6ZR37	460
ARHGEF33	ARHGEF40	Q8TER5	456
ARHGEF33	CDC42BPB	Q9Y5S2	456
ARHGEF33	ARHGEF5	Q12774	454
ARHGEF33	USP31	Q70CQ4	447
ARHGEF33	PLEKHG6	Q3KR16	447

IntAct

0 interactions, top by confidence:

BioGRID (5): ARHGEF33 (Affinity Capture-MS), ARHGEF33 (Affinity Capture-MS), ARHGEF33 (Affinity Capture-MS), ARHGEF33 (Affinity Capture-MS), RAN (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A0A6YY25, A0A5K7RLP0, A6NMK8, A8MVX0, B2RQL2, B2RXH4, C9JSJ3, D2J0Y4, O54824, P97303, Q01954, Q05AH6, Q0VET5, Q14005, Q1W617, Q2YDE2, Q3MHT3, Q3U0P1, Q3ULM6, Q3UXL4, Q4R7L6, Q5RC05, Q5T0L3, Q68CR7, Q6GQV1, Q6NS69, Q6NZK5, Q6P1D7, Q6PG16, Q6ZVT6, Q7Z4V0, Q80W88, Q80XI1, Q811R2, Q86T90, Q86YN6, Q8BHP2, Q8BLK9, Q8BP99, Q8BW86

Diamond homologs: A8MVX0, Q8BW86

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	128
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
2425393	NC_000002.11:g.(?37334416)(39347563_?)dup	Pathogenic
3062647	GRCh37/hg19 2p23.1-21(chr2:30814984-42798684)x1	Pathogenic
635956	NC_000002.11:g.39053852_42501893dup	Likely pathogenic

SpliceAI

2878 predictions. Top by Δscore:

Variant	Effect	Δscore
2:38889984:GGG:G	donor_gain	1.0000
2:38889985:GGG:G	donor_gain	1.0000
2:38889987:G:GA	donor_loss	1.0000
2:38889987:G:GG	donor_gain	1.0000
2:38889988:T:A	donor_loss	1.0000
2:38895771:TTACA:T	acceptor_gain	1.0000
2:38895772:TACA:T	acceptor_loss	1.0000
2:38895772:TACAG:T	acceptor_gain	1.0000
2:38895773:ACAG:A	acceptor_loss	1.0000
2:38895773:ACAGA:A	acceptor_gain	1.0000
2:38895774:C:G	acceptor_gain	1.0000
2:38895774:CA:C	acceptor_loss	1.0000
2:38895774:CAGAA:C	acceptor_gain	1.0000
2:38895775:A:AG	acceptor_gain	1.0000
2:38895776:G:GT	acceptor_gain	1.0000
2:38895776:GA:G	acceptor_gain	1.0000
2:38895776:GAA:G	acceptor_gain	1.0000
2:38895776:GAAC:G	acceptor_gain	1.0000
2:38895776:GAACT:G	acceptor_gain	1.0000
2:38895847:GAG:G	donor_gain	1.0000
2:38895848:AGGT:A	donor_loss	1.0000
2:38895849:GGTG:G	donor_loss	1.0000
2:38895850:G:GG	donor_gain	1.0000
2:38895850:GTG:G	donor_loss	1.0000
2:38895851:T:A	donor_loss	1.0000
2:38919352:T:A	acceptor_gain	1.0000
2:38919357:T:A	acceptor_gain	1.0000
2:38919362:GGTGC:G	acceptor_gain	1.0000
2:38919468:GCAAG:G	donor_gain	1.0000
2:38919469:C:T	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000013318 (2:38933183 G>A,C), RS1000033217 (2:38916941 C>T), RS1000036784 (2:38949585 A>G), RS1000056949 (2:38922491 T>C), RS1000079722 (2:38967143 C>T), RS1000155395 (2:38939313 G>A), RS1000159988 (2:38890252 G>A,T), RS1000188067 (2:38921094 A>G), RS1000216612 (2:38894046 G>C), RS1000225036 (2:38899087 T>A), RS1000253821 (2:38905174 T>C), RS1000276254 (2:38965940 C>A,T), RS1000286237 (2:38904996 C>A), RS1000295811 (2:38944645 C>G), RS1000410062 (2:38899342 G>A,C)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (2): RASopathy (MONDO:0021060), neurodevelopmental disorder (MONDO:0700092)

Orphanet (1): RASopathy (Orphanet:536391)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003465_9	Cannabis dependence symptom count	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008457	cannabis dependence measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
licochalcone B	increases expression	1
Benzo(a)pyrene	increases methylation	1
Testosterone	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

211 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
NCT04888936	Not specified	RECRUITING	Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies
NCT05761314	Not specified	RECRUITING	Solid Tumors in RASopathies
NCT06331117	Not specified	UNKNOWN	Effect of RAS/MAPK Pathway Hyperactivation on Growth’ and Bone’ Profile of the RASopathies
NCT06355622	Not specified	UNKNOWN	Prevalence and Characterization of Pain in RASopathies
NCT06489067	Not specified	RECRUITING	Study of the Thyroid Function and Echostructural Morphology in Patients Affected With Rasopathies (ECORAS2023)
NCT06776380	Not specified	RECRUITING	Pubertal Development in Patients with RASopathies
NCT07005297	Not specified	NOT_YET_RECRUITING	Clinical Genetics Branch Eligibility Screening Survey
NCT07344480	Not specified	RECRUITING	Retrospective Natural History Study of RASopathy-associated Cardiomyopathy (RAS-CM)
NCT07464821	Not specified	RECRUITING	National Multicentre Study on Lipid Profile in Noonan Syndrome and Related Disorders: Trends by Age, Gender and Genotype
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