RHOH

Summary

RHOH (ras homolog family member H, HGNC:686) is a protein-coding gene on chromosome 4p14, encoding Rho-related GTP-binding protein RhoH (Q15669). Negative regulator of hematopoietic progenitor cell proliferation, survival and migration.

The protein encoded by this gene is a member of the Ras superfamily of guanosine triphosphate (GTP)-metabolizing enzymes. The encoded protein is expressed in hematopoietic cells, where it functions as a negative regulator of cell growth and survival. This gene may be hypermutated or misexpressed in leukemias and lymphomas. Chromosomal translocations in non-Hodgkin’s lymphoma occur between this locus and B-cell CLL/lymphoma 6 (BCL6) on chromosome 3, leading to the production of fusion transcripts. Alternative splicing in the 5’ untranslated region results in multiple transcript variants that encode the same protein.

Source: NCBI Gene 399 — RefSeq curated summary.

At a glance

• Gene–disease (curated): epidermodysplasia verruciformis, susceptibility to, 4 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 98 total
• Phenotypes (HPO): 8
• MANE Select transcript: NM_004310

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:686
Approved symbol	RHOH
Name	ras homolog family member H
Location	4p14
Locus type	gene with protein product
Status	Approved
Aliases	TTF
Ensembl gene	ENSG00000168421
Ensembl biotype	protein_coding
OMIM	602037
Entrez	399

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 26 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000381799, ENST00000503754, ENST00000503941, ENST00000503978, ENST00000504638, ENST00000505618, ENST00000507851, ENST00000508513, ENST00000511121, ENST00000511967, ENST00000513894, ENST00000514143, ENST00000514839, ENST00000515503, ENST00000515702, ENST00000515718, ENST00000614836, ENST00000908158, ENST00000908159, ENST00000908160, ENST00000908161, ENST00000908162, ENST00000908163, ENST00000908164, ENST00000919405, ENST00000919406, ENST00000919407, ENST00000962316, ENST00000962317

RefSeq mRNA: 12 — MANE Select: NM_004310 NM_001278359, NM_001278360, NM_001278361, NM_001278362, NM_001278363, NM_001278364, NM_001278365, NM_001278366, NM_001278367, NM_001278368, NM_001278369, NM_004310

CCDS: CCDS3458

Canonical transcript exons

ENST00000381799 — 3 exons

Exon	Start	End
ENSE00001122975	40243178	40246967
ENSE00001170796	40242714	40242834
ENSE00003845075	40197031	40197300

Expression profiles

Bgee: expression breadth ubiquitous, 174 present calls, max score 93.88.

FANTOM5 (CAGE): breadth broad, TPM avg 22.4986 / max 1023.3252, expressed in 583 samples.

FANTOM5 promoters (19 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47415	18.9564	458
47416	1.4140	184
47414	0.3734	115
47404	0.3230	84
47421	0.2525	114
47408	0.2214	45
47431	0.1875	67
47402	0.1653	51
47417	0.1429	59
47412	0.1367	59

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bone marrow cell	CL:0002092	93.88	gold quality
lymph node	UBERON:0000029	93.61	gold quality
vermiform appendix	UBERON:0001154	93.43	gold quality
granulocyte	CL:0000094	93.33	gold quality
thymus	UBERON:0002370	92.65	gold quality
spleen	UBERON:0002106	92.13	gold quality
bone marrow	UBERON:0002371	91.13	gold quality
blood	UBERON:0000178	90.73	gold quality
epithelium of nasopharynx	UBERON:0001951	86.56	gold quality
caecum	UBERON:0001153	86.08	gold quality
tonsil	UBERON:0002372	83.44	gold quality
colonic epithelium	UBERON:0000397	82.11	gold quality
type B pancreatic cell	CL:0000169	81.01	gold quality
olfactory bulb	UBERON:0002264	80.89	gold quality
gall bladder	UBERON:0002110	80.85	gold quality
small intestine Peyer’s patch	UBERON:0003454	80.70	gold quality
ileal mucosa	UBERON:0000331	80.43	silver quality
mucosa of transverse colon	UBERON:0004991	79.49	gold quality
rectum	UBERON:0001052	79.40	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.16	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.68	gold quality
small intestine	UBERON:0002108	78.11	gold quality
leukocyte	CL:0000738	76.41	gold quality
superficial temporal artery	UBERON:0001614	76.36	gold quality
diaphragm	UBERON:0001103	76.00	gold quality
mononuclear cell	CL:0000842	74.61	gold quality
upper lobe of left lung	UBERON:0008952	74.34	gold quality
monocyte	CL:0000576	74.05	gold quality
upper lobe of lung	UBERON:0008948	73.74	gold quality
smooth muscle tissue	UBERON:0001135	72.91	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	584.25
E-HCAD-4	yes	93.54
E-CURD-122	yes	33.93
E-GEOD-135922	yes	33.70
E-MTAB-8410	yes	21.87
E-CURD-112	yes	3.86
E-MTAB-7303	no	488.04
E-MTAB-5061	no	3.67
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA3, GLI2, JUND, POU2F3, STAT3, STAT5A, ZBED1

miRNA regulators (miRDB)

36 targeting RHOH, 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-3646	100.00	73.56	5283
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-2682-5P	99.73	67.38	1055
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-651-5P	99.64	68.49	1104
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-5689	99.50	71.26	1154
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-3606-5P	99.31	69.67	1168
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-8065	99.19	70.38	1289
HSA-MIR-4426	99.17	66.74	1949
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-7854-3P	99.08	66.26	1117
HSA-MIR-4711-3P	98.97	66.87	1020
HSA-MIR-1257	98.97	68.02	1133
HSA-MIR-421	98.90	67.04	1883
HSA-MIR-3150B-3P	98.81	67.21	1728
HSA-MIR-4662B	98.33	66.37	1163
HSA-MIR-4647	98.30	66.41	1139
HSA-MIR-4684-5P	98.29	67.99	1650
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-660-5P	98.16	68.27	680
HSA-MIR-6819-5P	97.96	66.59	1071

Literature-anchored findings (GeneRIF, showing 22)

• 5’ end heterogeneity of RhoH mRNAs was observed, due to alternative splicing of some 5’ exons and to the use of these different transcription start sites. (PMID:15563831)
• In both Richter’s transformation and prolymphocytic transformation, high-levels of AID mRNA expression and high-frequency mutations of RhoH protein genes were detected. (PMID:16541139)
• Aberrant somatic hypermutation of RhoH gene is associated with diffuse large B cell lymphoma (PMID:17443219)
• RHOH mutation is associated with splenic and nodal marginal zone B-cell lymphomas (PMID:17476282)
• Underexpression of RhoH is associated with Hairy Cell Leukemia (PMID:18559497)
• low expression of the RhoH transcript was a predictor of worse prognosis in both overall and disease-free survival. (PMID:18691253)
• RhoH/TTF represents an inducible feedback inhibitor in neutrophils that is involved in the limitation of innate immune responses. (PMID:19414807)
• RhoH has a function in the progression of B-cell chronic lymphocytic leukemia (CLL) in a murine model and show RhoH expression is altered in human primary lymphocytic (CLL) samples. (PMID:19847197)
• Data suggest that RhoH function might be regulated by lysosomal degradation of RhoH protein following TCR complex but not BCR activation. (PMID:19950172)
• propose that RhoH functions as a negative regulator for IL3-induced signals through modulation of the JAK-STAT pathway (PMID:20738848)
• RhoH is a key adapter protein that maintains LCK in the inactive state, contributing to the regulation of both pre-TCR and TCR signalling during T-cell development. (PMID:20851766)
• Repression of the RHOH gene by JunD (PMID:21473742)
• RhoH plays a critical role in prosurvival chronic lymphocytic leukemia cell-cell and cell-microenvironment interactions with this agent. (PMID:22474251)
• conclude that RhoH expression provides a key molecular determinant that allows T cells to switch between sensing chemokine-mediated go signals and TCR-dependent stop signals (PMID:22689994)
• RHOH deficiency leads to T cell defects and persistent epidermodysplasia verruciformis-HPV infections. (PMID:22850876)
• Our current results indicate differential requirements for RhoH in the development of TCRalphabeta CD8alphaalpha IELs compared to other subsets of T cells including agonist selected T cells. (PMID:23499578)
• Mutations in hematopoiesis-specific Rho GTPases Rac2 and RhoH lead to a wide range of human blood disorders. (Review) (PMID:23850828)
• extracellular microenvironment signals regulate RhoH and Kaiso to modulate actin-cytoskeleton structure and transcriptional activity during T cell migration (PMID:27574848)
• These results highlight a novel negative regulatory role for RhoH in eosinophil differentiation, most likely in consequence of altered GATA-2 levels. (PMID:27740624)
• RhoH promotes prostate cancer cell migration and RhoH expression levels correlate with prostate cancer progression. (PMID:29510700)
• In AML, RhoH expression negatively correlates with recurrence rate, which can be used as a prognostic indicator independently (PMID:31204928)
• Weighted gene co-expression network analysis identifies RHOH and TRAF1 as key candidate genes for psoriatic arthritis. (PMID:32959187)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rhoh	ENSDARG00000070121
mus_musculus	Rhoh	ENSMUSG00000029204
rattus_norvegicus	Rhoh	ENSRNOG00000002540

Paralogs (22): RHOBTB2 (ENSG00000008853), RHOA (ENSG00000067560), CDC42 (ENSG00000070831), RHOBTB1 (ENSG00000072422), RHOV (ENSG00000104140), RND2 (ENSG00000108830), RND3 (ENSG00000115963), RHOU (ENSG00000116574), RHOQ (ENSG00000119729), RHOJ (ENSG00000126785), RHOT1 (ENSG00000126858), RAC2 (ENSG00000128340), RAC1 (ENSG00000136238), RHOF (ENSG00000139725), RHOT2 (ENSG00000140983), RHOB (ENSG00000143878), RHOC (ENSG00000155366), RHOBTB3 (ENSG00000164292), RAC3 (ENSG00000169750), RND1 (ENSG00000172602), RHOD (ENSG00000173156), RHOG (ENSG00000177105)

Protein

Protein identifiers

Rho-related GTP-binding protein RhoH — Q15669 (reviewed: Q15669)

Alternative names: GTP-binding protein TTF, Translocation three four protein

All UniProt accessions (5): Q15669, D6R8Z1, D6RA52, D6RG23, Q6ICP4

UniProt curated annotations — full annotation on UniProt →

Function. Negative regulator of hematopoietic progenitor cell proliferation, survival and migration. Critical regulator of thymocyte development and T-cell antigen receptor (TCR) signaling by mediating recruitment and activation of ZAP70. Required for phosphorylation of CD3Z, membrane translocation of ZAP70 and subsequent activation of the ZAP70-mediated pathways. Essential for efficient beta-selection and positive selection by promoting the ZAP70-dependent phosphorylation of the LAT signalosome during pre-TCR and TCR signaling. Crucial for thymocyte maturation during DN3 to DN4 transition and during positive selection. Plays critical roles in mast cell function by facilitating phosphorylation of SYK in Fc epsilon RI-mediated signal transduction. Essential for the phosphorylation of LAT, LCP2, PLCG1 and PLCG2 and for Ca(2+) mobilization in mast cells. Binds GTP but lacks intrinsic GTPase activity and is resistant to Rho-specific GTPase-activating proteins. Inhibits the activation of NF-kappa-B by TNF and IKKB and the activation of CRK/p38 by TNF. Inhibits activities of RAC1, RHOA and CDC42. Negatively regulates leukotriene production in neutrophils.

Subunit / interactions. Interacts with ZAP70 (via SH2 domains) and the interaction is enhanced by its phosphorylation by LCK. Interacts with SYK and the interaction is enhanced by its phosphorylation by FYN. Interacts with GDI1 and GDI2. Interacts with PAK5.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Expressed only in hematopoietic cells. Present at very high levels in the thymus, less abundant in the spleen, and least abundant in the bone marrow. Expressed at a higher level in the TH1 subtype of T-helper cells than in the TH2 subpopulation. Expressed in neutrophils under inflammatory conditions, such as cystic fibrosis, ulcerative colitis and appendicitis.

Post-translational modifications. Phosphorylated on tyrosine by LCK. Phosphorylated by FYN. Phosphorylation enhances the interactions with ZAP70 and SYK and is critical for its function in thymocyte development.

Disease relevance. A chromosomal aberration involving RHOH is found in a non-Hodgkin lymphoma cell line. Translocation t(3;4)(q27;p11) with BCL6. Immunodeficiency 129 (IMD129) [MIM:618307] An autosomal recessive immunologic disorder characterized by recurrent bacterial, viral, and fungal infections beginning in the first or second decades of life. Some patients have an abnormal susceptibility to infection by specific human papillomaviruses, including the oncogenic HPV5. Infection leads to the early development of disseminated flat wart-like and pityriasis versicolor-like skin lesions. Cutaneous Bowen’s carcinomas in situ and invasive squamous cell carcinomas develop in about half of the patients, mainly on sun-exposed skin areas. Affected individuals have decreased number of naive T cells, increased memory and effector T cells, and impaired T-cell receptor signaling. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The region involved in interaction with ZAP70 is a non-canonical immunoreceptor tyrosine-based activation motif (ITAM).

Induction. By CSF2/GM-CSF. Down-regulated by phorbol myristate acetate (PMA).

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

RefSeq proteins (12): NP_001265288, NP_001265289, NP_001265290, NP_001265291, NP_001265292, NP_001265293, NP_001265294, NP_001265295, NP_001265296, NP_001265297, NP_001265298, NP_004301* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001806	Small_GTPase	Family
IPR003578	Small_GTPase_Rho	Family
IPR005225	Small_GTP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00071

Enzyme classification (BRENDA):

• EC 3.6.5.2 — small monomeric GTPase (BRENDA: 49 organisms, 138 substrates, 55 inhibitors, 5 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GTP	—	0

UniProt features (10 total): binding site 3, chain 1, propeptide 1, region of interest 1, short sequence motif 1, modified residue 1, lipid moiety-binding region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15669-F1	92.81	0.78

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 (3): 11–18; 58–62; 116–119

Post-translational modifications (2): 188, 188

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9013407	RHOH GTPase cycle

MSigDB gene sets: 407 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, GOMF_GTPASE_BINDING, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, PUJANA_CHEK2_PCC_NETWORK, GOBP_CELL_CELL_ADHESION, HOFMANN_MYELODYSPLASTIC_SYNDROM_RISK_DN, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION, GOBP_MAST_CELL_ACTIVATION

GO Biological Process (8): regulation of DNA-templated transcription (GO:0006355), actin filament organization (GO:0007015), signal transduction (GO:0007165), small GTPase-mediated signal transduction (GO:0007264), T cell differentiation (GO:0030217), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), mast cell activation (GO:0045576), positive regulation of T cell differentiation (GO:0045582)

GO Molecular Function (8): GTPase activity (GO:0003924), GTPase inhibitor activity (GO:0005095), GTP binding (GO:0005525), kinase inhibitor activity (GO:0019210), protein kinase binding (GO:0019901), small GTPase binding (GO:0031267), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (4): immunological synapse (GO:0001772), cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RHO GTPase cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
enzyme inhibitor activity	2
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
intracellular signaling cassette	1
lymphocyte differentiation	1
T cell activation	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
negative regulation of intracellular signal transduction	1
myeloid leukocyte activation	1
T cell differentiation	1
regulation of T cell differentiation	1
positive regulation of lymphocyte differentiation	1
positive regulation of T cell activation	1
ribonucleoside triphosphate phosphatase activity	1
GTPase activity	1
GTPase regulator activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
kinase activity	1
kinase regulator activity	1
kinase binding	1
GTPase binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
plasma membrane	1
intracellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

3475 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RHOH	PAX5	Q02548	847
RHOH	BCL6	P41182	809
RHOH	AICDA	Q9GZX7	749
RHOH	LCK	P06239	730
RHOH	ZAP70	P43403	637
RHOH	MYC	P01106	603
RHOH	IGHV4-38-2	P0DP08	587
RHOH	POU2AF1	Q16633	584
RHOH	ICAM3	P32942	564
RHOH	ICAM2	P13598	560
RHOH	CD79B	P40259	555
RHOH	FAS	P25445	552
RHOH	CD79A	P11912	537
RHOH	IKZF1	Q13422	532
RHOH	SYK	P43405	530

IntAct

57 interactions, top by confidence:

A	B	Type	Score
SUOX	RHOH	psi-mi:“MI:0915”(physical association)	0.560
PLEKHG5	RHOH	psi-mi:“MI:0915”(physical association)	0.560
IQUB	RHOH	psi-mi:“MI:0915”(physical association)	0.560
ITGB1BP1	RHOH	psi-mi:“MI:0915”(physical association)	0.560
FAM90A1	RHOH	psi-mi:“MI:0915”(physical association)	0.560
CCNH	RHOH	psi-mi:“MI:0915”(physical association)	0.560
RHOH	XPNPEP1	psi-mi:“MI:0915”(physical association)	0.560
RHOH	IQUB	psi-mi:“MI:0915”(physical association)	0.560
RHOH	TCF19	psi-mi:“MI:0915”(physical association)	0.560
RHOH	PLEKHA7	psi-mi:“MI:0915”(physical association)	0.560
RHOH	BANP	psi-mi:“MI:0915”(physical association)	0.560
	RHOH	psi-mi:“MI:0915”(physical association)	0.560
RHOH	KANK2	psi-mi:“MI:0915”(physical association)	0.560
RHOH	FAM90A1	psi-mi:“MI:0915”(physical association)	0.560
RIPPLY1	RHOH	psi-mi:“MI:0915”(physical association)	0.560
MTX2	RHOH	psi-mi:“MI:0915”(physical association)	0.560
RHOH	SCNM1	psi-mi:“MI:0915”(physical association)	0.560
RHOH	SORL1	psi-mi:“MI:0915”(physical association)	0.560
RHOH	H2AC4	psi-mi:“MI:0915”(physical association)	0.400
RHOH	HMGN2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (512): ZBTB33 (Affinity Capture-Western), ZBTB33 (Co-localization), CTNND1 (Affinity Capture-Western), CTNND1 (Co-localization), ZBTB33 (Affinity Capture-MS), ZAP70 (Affinity Capture-MS), LCK (Affinity Capture-MS), LRIF1 (Two-hybrid), UTP14A (Two-hybrid), RHOH (Two-hybrid), RHOH (Two-hybrid), RHOH (Two-hybrid), RHOH (Two-hybrid), RHOH (Two-hybrid), RHOH (Two-hybrid)

ESM2 similar proteins: D3Z8L7, E2RQ15, O00212, O13928, O77683, P06781, P10833, P35278, P46629, P51146, P51147, P51148, P52198, P57735, P61017, P61018, P61587, P61588, P97348, Q06AU6, Q0PD08, Q15669, Q1RMR4, Q23862, Q2HJ68, Q2HJG3, Q32NQ0, Q3SZA1, Q3ZC27, Q58DS9, Q58DW6, Q5R7L7, Q5R9F4, Q6SA80, Q86YS6, Q874R1, Q8BLR7, Q8BYP3, Q91ZR1, Q96AX2

Diamond homologs: B7U179, O43791, O94955, O95199, Q0VCW1, Q15669, Q2HJG3, Q5NVK7, Q5RCZ7, Q6NXM2, Q6P798, Q6ZWS8, Q7T330, Q8NDN9, Q91V93, Q99LJ7, Q9CTN4, Q9D3G9, Q9XHZ8, A0A286QZ36, O00212, O04369, O13928, O42825, O76321, O82480, O88931, O96390, P01122, P06780, P06781, P08134, P15153, P22122, P24406, P34144, P34145, P34146, P34147, P34148

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
RHOH	“up-regulates activity”	ZAP70	binding
RHOH	“down-regulates activity”	RAC1	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	40
Likely benign	48
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1107 predictions. Top by Δscore:

Variant	Effect	Δscore
4:40208182:A:AG	acceptor_gain	1.0000
4:40242711:CAGTT:C	acceptor_loss	1.0000
4:40242712:A:AG	acceptor_gain	1.0000
4:40242712:AGT:A	acceptor_loss	1.0000
4:40242713:G:GC	acceptor_gain	1.0000
4:40242713:GT:G	acceptor_gain	1.0000
4:40242713:GTTTC:G	acceptor_gain	1.0000
4:40242709:TGCAG:T	acceptor_gain	0.9900
4:40242713:GTT:G	acceptor_gain	0.9900
4:40242713:GTTT:G	acceptor_gain	0.9900
4:40242863:A:AG	donor_gain	0.9900
4:40242864:G:GG	donor_gain	0.9900
4:40243176:A:AG	acceptor_gain	0.9900
4:40243177:G:GA	acceptor_gain	0.9900
4:40197118:CAG:C	acceptor_gain	0.9800
4:40197119:A:T	acceptor_gain	0.9800
4:40197120:G:T	acceptor_gain	0.9800
4:40242708:TTGCA:T	acceptor_gain	0.9800
4:40242710:GCAGT:G	acceptor_gain	0.9800
4:40242784:G:GT	donor_gain	0.9800
4:40243177:GTT:G	acceptor_gain	0.9800
4:40197117:TCA:T	acceptor_gain	0.9700
4:40242711:CAG:C	acceptor_gain	0.9700
4:40243170:T:TA	acceptor_gain	0.9700
4:40243177:GTTGA:G	acceptor_gain	0.9700
4:40191334:ATAAG:A	donor_loss	0.9600
4:40191335:TAAGG:T	donor_loss	0.9600
4:40191336:AAGG:A	donor_loss	0.9600
4:40191337:AG:A	donor_loss	0.9600
4:40191338:GG:G	donor_loss	0.9600

AlphaMissense

1250 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:40243559:A:C	D58A	0.998
4:40243436:A:T	K17I	0.997
4:40243439:C:T	T18I	0.997
4:40243559:A:T	D58V	0.997
4:40243432:G:T	G16W	0.996
4:40243435:A:C	K17Q	0.996
4:40243437:A:C	K17N	0.996
4:40243437:A:T	K17N	0.996
4:40243558:G:C	D58H	0.996
4:40243883:C:A	A166D	0.996
4:40243433:G:A	G16E	0.995
4:40243433:G:T	G16V	0.995
4:40243559:A:G	D58G	0.995
4:40243630:T:C	C82R	0.995
4:40243632:C:G	C82W	0.995
4:40243678:T:A	W98R	0.995
4:40243678:T:C	W98R	0.995
4:40243792:G:T	G136W	0.995
4:40243405:T:C	C7R	0.994
4:40243418:G:T	G11V	0.994
4:40243432:G:A	G16R	0.994
4:40243432:G:C	G16R	0.994
4:40243471:T:C	F29L	0.994
4:40243473:C:A	F29L	0.994
4:40243473:C:G	F29L	0.994
4:40243560:C:A	D58E	0.994
4:40243560:C:G	D58E	0.994
4:40243727:T:A	V114E	0.994
4:40243730:C:A	A115D	0.994
4:40243839:C:G	C151W	0.994

dbSNP variants (sampled 300 via entrez): RS1000074072 (4:40220556 A>G,T), RS1000074883 (4:40211200 T>G), RS1000216109 (4:40232835 C>G), RS1000240640 (4:40233208 A>T), RS1000402498 (4:40194719 G>A,C), RS1000433625 (4:40194288 G>A,C), RS1000452438 (4:40239091 C>T), RS1000494030 (4:40227176 C>A,T), RS1000514294 (4:40205389 G>A,T), RS1000554995 (4:40231465 A>G), RS1000588986 (4:40231668 G>A), RS1000603783 (4:40190691 T>C,G), RS1000675779 (4:40244492 A>G), RS1000684669 (4:40196313 A>G), RS1000854456 (4:40207909 T>C)

Disease associations

OMIM: gene MIM:602037 | disease phenotypes: MIM:618307

GenCC curated gene-disease

Disease	Classification	Inheritance
epidermodysplasia verruciformis, susceptibility to, 4	Strong	Autosomal recessive
epidermodysplasia verruciformis	Moderate	Autosomal recessive
T-cell immunodeficiency with epidermodysplasia verruciformis	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
epidermodysplasia verruciformis, susceptibility to, 4	Moderate	AR

Mondo (3): T-cell immunodeficiency with epidermodysplasia verruciformis (MONDO:0017925), epidermodysplasia verruciformis, susceptibility to, 4 (MONDO:0032666), epidermodysplasia verruciformis (MONDO:0009176)

Orphanet (1): T-cell immunodeficiency with epidermodysplasia verruciformis (Orphanet:324294)

HPO phenotypes

8 total (8 of 8 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001041	Facial erythema
HP:0002097	Emphysema
HP:0010280	Stomatitis
HP:0011463	Childhood onset
HP:0030080	Burkitt lymphoma
HP:0031514	Increased proportion of exhausted T cells
HP:0032215	Disseminated cutaneous warts

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001200_4	Graves’ disease	1.000000e-13
GCST008758_45	Pre-treatment viral load in HIV-1 infection	7.000000e-16
GCST009391_998	Metabolite levels	1.000000e-06
GCST009597_111	Multiple sclerosis	8.000000e-10
GCST009597_270	Multiple sclerosis	6.000000e-07
GCST010396_80	Gut microbiota (bacterial taxa, hurdle binary method)	8.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0010125	viral load
EFO:0010540	thiamine measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D004819	Epidermodysplasia Verruciformis	C01.925.256.650.810.345; C01.925.825.810.260; C01.925.928.914.345; C17.800.838.790.810.260

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Nickel	increases expression	3
(+)-JQ1 compound	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	increases expression, decreases expression	2
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bis(tri-n-butyltin)oxide	decreases expression	1
bisphenol A	decreases methylation	1
deoxynivalenol	increases expression	1
trichostatin A	decreases expression	1
tetrachlorodian	increases expression	1
15-acetyldeoxynivalenol	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	increases reaction, affects binding	1
2-palmitoylglycerol	increases expression	1
entinostat	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
bisphenol S	decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Arsenic Trioxide	increases expression	1
Panobinostat	decreases expression, affects cotreatment	1
Air Pollutants, Occupational	increases expression	1
Anisomycin	increases expression	1
Arsenic	decreases expression, decreases methylation	1
Benzo(a)pyrene	increases methylation	1
Benzoates	increases expression	1
Cisplatin	increases expression	1
Methyl Methanesulfonate	decreases expression	1
Methylcholanthrene	affects binding, increases reaction	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00973856	Not specified	COMPLETED	Evaluation of the Effectiveness of an Alcohol Based Hand Gel for the Reduction of Warts on the Hands