STEAP3

Summary

STEAP3 (STEAP3 metalloreductase, HGNC:24592) is a protein-coding gene on chromosome 2q14.2, encoding Metalloreductase STEAP3 (Q658P3). Integral membrane protein that functions as a NADPH-dependent ferric-chelate reductase, using NADPH from one side of the membrane to reduce a Fe(3+) chelate that is bound on the other side of the membrane.

This gene encodes a multipass membrane protein that functions as an iron transporter. The encoded protein can reduce both iron (Fe3+) and copper (Cu2+) cations. This protein may mediate downstream responses to p53, including promoting apoptosis. Deficiency in this gene can cause anemia. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 55240 — RefSeq curated summary.

At a glance

• Gene–disease (curated): severe congenital hypochromic anemia with ringed sideroblasts (Moderate, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 189 total — 1 pathogenic
• Phenotypes (HPO): 29
• MANE Select transcript: NM_182915

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24592
Approved symbol	STEAP3
Name	STEAP3 metalloreductase
Location	2q14.2
Locus type	gene with protein product
Status	Approved
Aliases	TSAP6, dudlin-2, STMP3
Ensembl gene	ENSG00000115107
Ensembl biotype	protein_coding
OMIM	609671
Entrez	55240

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 14 protein_coding

ENST00000393106, ENST00000393107, ENST00000393110, ENST00000409811, ENST00000869398, ENST00000869399, ENST00000869400, ENST00000869401, ENST00000869402, ENST00000869403, ENST00000869404, ENST00000869405, ENST00000869406, ENST00000869407

RefSeq mRNA: 4 — MANE Select: NM_182915 NM_001008410, NM_018234, NM_138637, NM_182915

CCDS: CCDS2125, CCDS42738, CCDS82504

Canonical transcript exons

ENST00000393110 — 6 exons

Exon	Start	End
ENSE00001385589	119263057	119265652
ENSE00001726104	119247679	119248206
ENSE00002488032	119254684	119254848
ENSE00003491214	119245489	119245988
ENSE00003647425	119230620	119231034
ENSE00003841421	119223834	119223888

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 97.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.0214 / max 284.4917, expressed in 1687 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
22259	21.0214	1687

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	97.35	gold quality
liver	UBERON:0002107	95.73	gold quality
dorsal root ganglion	UBERON:0000044	94.77	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.21	gold quality
epithelium of bronchus	UBERON:0002031	92.53	gold quality
bronchus	UBERON:0002185	92.07	gold quality
bronchial epithelial cell	CL:0002328	91.95	gold quality
mammary duct	UBERON:0001765	91.80	gold quality
trigeminal ganglion	UBERON:0001675	91.09	gold quality
triceps brachii	UBERON:0001509	90.73	gold quality
nasal cavity mucosa	UBERON:0001826	89.59	gold quality
epithelium of mammary gland	UBERON:0003244	89.39	gold quality
biceps brachii	UBERON:0001507	89.20	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	88.93	gold quality
diaphragm	UBERON:0001103	88.89	gold quality
vastus lateralis	UBERON:0001379	88.44	gold quality
mucosa of transverse colon	UBERON:0004991	88.34	gold quality
parotid gland	UBERON:0001831	88.17	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.07	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	87.49	gold quality
saliva-secreting gland	UBERON:0001044	87.21	gold quality
quadriceps femoris	UBERON:0001377	87.07	gold quality
gluteal muscle	UBERON:0002000	86.76	gold quality
cardia of stomach	UBERON:0001162	86.71	gold quality
minor salivary gland	UBERON:0001830	86.69	gold quality
body of pancreas	UBERON:0001150	86.49	gold quality
skeletal muscle tissue	UBERON:0001134	86.26	gold quality
muscle organ	UBERON:0001630	86.16	gold quality
gastrocnemius	UBERON:0001388	86.15	gold quality
mucosa of paranasal sinus	UBERON:0005030	86.04	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.86

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

92 targeting STEAP3, 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-9-5P	100.00	72.28	2361
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-557	99.96	70.01	1640
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-4271	99.88	68.32	2244

Literature-anchored findings (GeneRIF, showing 17)

• TSAP6 may augment Myt1 activity and act downstream to p53 to interface apoptosis and cell-cycle progression (PMID:12606722)
• role for TSAP6 in the export of TCTP and indicate that this multipass membrane protein could have a general role in the regulation of vesicular trafficking and secretion. (PMID:15319436)
• The crystal structure of the human Steap3 oxidoreductase domain in the absence and presence of NADPH was determined. (PMID:18495927)
• Down-regulated expression of the TSAP6 protein in liver is associated with a transition from cirrhosis to hepatocellular carcinoma (PMID:19236508)
• findings indicate that STEAP3 maintains iron storage in human malignant cells and tumor proliferation under the hypoferric condition (PMID:21871451)
• TSAP6 is a target of rhomboid protease RHBDD1-induced proteolysis. (PMID:22624035)
• heterozygous STEAP3 mutations are relatively common in humans and that their deleterious effect in humans remains to be confirmed (PMID:26675350)
• TSAP6 over expression is associated with poor survival in metastatic high-grade serous carcinoma. (PMID:27825812)
• In hepatocellular carcinoma (HCC), lower expression of the STEAP3 copper reductase and heavy Cu isotope enrichment have been reported for the tumor mass, relative to the surrounding tissue (PMID:28303916)
• this study identified oxidative stress-dependent upregulation of the iron-converting metalloreductase, STEAP3, as a key mediator of extracellular matrix production in wound healing (PMID:31176711)
• This article is the first report of a role of Steap3 in mature RBCs; it defines a new mechanism of redox biology in RBCs with a substantial effect upon RBC function and provides a novel mechanistic determinant of genetic variation of RBC storage. (PMID:31350307)
• Predictive potential of STEAP family for survival, immune microenvironment and therapy response in glioma. (PMID:34649092)
• STEAP3 promotes cancer cell proliferation by facilitating nuclear trafficking of EGFR to enhance RAC1-ERK-STAT3 signaling in hepatocellular carcinoma. (PMID:34741044)
• STEAP3 Affects Ferroptosis and Progression of Renal Cell Carcinoma Through the p53/xCT Pathway. (PMID:35275508)
• Six-Transmembrane Epithelial Antigen of Prostate 3 Promotes Hepatic Insulin Resistance and Steatosis. (PMID:36495944)
• STEAP3 Affects Ovarian Cancer Progression by Regulating Ferroptosis through the p53/SLC7A11 Pathway. (PMID:38440354)
• STEAP3 promotes colon cancer cell proliferation and migration via regulating histone acetylation. (PMID:38480539)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	steap3	ENSDARG00000075641
mus_musculus	Steap3	ENSMUSG00000026389
rattus_norvegicus	Steap3	ENSRNOG00000049471

Paralogs (4): STEAP1B (ENSG00000105889), STEAP4 (ENSG00000127954), STEAP2 (ENSG00000157214), STEAP1 (ENSG00000164647)

Protein

Protein identifiers

Metalloreductase STEAP3 — Q658P3 (reviewed: Q658P3)

Alternative names: Dudulin-2, Six-transmembrane epithelial antigen of prostate 3, Tumor suppressor-activated pathway protein 6, pHyde

All UniProt accessions (2): B8ZZX6, Q658P3

UniProt curated annotations — full annotation on UniProt →

Function. Integral membrane protein that functions as a NADPH-dependent ferric-chelate reductase, using NADPH from one side of the membrane to reduce a Fe(3+) chelate that is bound on the other side of the membrane. Mediates sequential transmembrane electron transfer from NADPH to FAD and onto heme, and finally to the Fe(3+) chelate. Can also reduce Cu(2+) to Cu(1+). Mediates efficient transferrin-dependent iron uptake in erythroid cells. May play a role downstream of p53/TP53 to interface apoptosis and cell cycle progression. Indirectly involved in exosome secretion by facilitating the secretion of proteins such as TCTP.

Subunit / interactions. Homodimer. Interacts with BNIP3L, MYT1, RHBDL4/RHBDD1 and TCTP.

Subcellular location. Endosome membrane.

Tissue specificity. Expressed in adult bone marrow, placenta, liver, skeletal muscle and pancreas. Down-regulated in hepatocellular carcinoma.

Post-translational modifications. Proteolytically cleaved by RHBDL4/RHBDD1. RHBDL4/RHBDD1-induced cleavage occurs at multiple sites in a glycosylation-independent manner. Glycosylated.

Disease relevance. Anemia, hypochromic microcytic, with iron overload 2 (AHMIO2) [MIM:615234] A hematologic disease characterized by abnormal hemoglobin content in the erythrocytes which are reduced in size, severe anemia, erythropoietic hyperplasia of bone marrow, massive hepatic iron deposition, and hepatosplenomegaly. The disease is caused by variants affecting the gene represented in this entry.

Induction. By p53/TP53.

Similarity. Belongs to the STEAP family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q658P3-1	1	yes
Q658P3-2	2
Q658P3-3	3
Q658P3-4	4, pHyde II

RefSeq proteins (4): NP_001008410, NP_060704, NP_619543, NP_878919* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013130	Fe3_Rdtase_TM_dom	Domain
IPR028939	P5C_Rdtase_cat_N	Domain
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR051267	STEAP_metalloreductase	Family

Pfam: PF01794, PF03807

Catalyzed reactions (Rhea), 2 shown:

• 2 Fe(2+) + NADP(+) + H(+) = 2 Fe(3+) + NADPH (RHEA:71767)
• 2 Cu(+) + NADP(+) + H(+) = 2 Cu(2+) + NADPH (RHEA:71771)

UniProt features (87 total): mutagenesis site 20, binding site 16, helix 12, strand 8, topological domain 7, transmembrane region 6, modified residue 5, sequence conflict 4, splice variant 3, glycosylation site 2, chain 1, domain 1, site 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2VNS	X-RAY DIFFRACTION	2
2VQ3	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q658P3-F1	89.24	0.81

Functional residue map

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

Catalytic / active sites (1): 325–326 (cleavage; by rhbdl4/rhbdd1)

Ligand- & substrate-binding residues (16): 36–39; 58–59; 91–98; 116; 151; 152; 160; 229; 281; 302; 303; 316 (axial binding residue) …

Post-translational modifications (5): 11, 17, 20, 474, 486

Glycosylation sites (2): 256, 344

Mutagenesis-validated functional residues (20):

Position	Phenotype
229	2.5-fold increase in km for fe(+3).
229	3-fold increase in km for fe(+3). 5-fold increase in km for fe(+3); when associated with f-319.
256	inhibits glycosylation and does not inhibit rhbdl4/rhbdd1-induced cleavage; when associated with a-344.
281	loss of ferric-chelate reductase activity.
287	loss of ferric-chelate reductase activity.
295	loss of ferric-chelate reductase activity.
298	2.5-fold increase in km for fad.
302	3-fold increase in km for fad.
302	loss of ferric-chelate reductase activity.
303	3-fold increase in km for fad.
303	5-fold increase in km for fad.
316	loss of ferric-chelate reductase activity and heme b-binding.
319	2-fold increase in km for fe(+3).
319	3-fold increase in km for fe(+3). 5-fold increase in km for fe(+3); when associated with f-229.
325	strongly inhibits rhbdl4/rhbdd1-induced cleavage.
344	inhibits glycosylation and does not inhibit rhbdl4/rhbdd1-induced cleavage; when associated with a-256.
388	3-fold increase in km for fad.
390	5-fold increase in km for fad.
395	20-fold increase in km for fad.
409	loss of ferric-chelate reductase activity and heme b-binding.

Function

Pathways and Gene Ontology

Reactome pathways

18 pathways

ID	Pathway
R-HSA-6803204	TP53 Regulates Transcription of Genes Involved in Cytochrome C Release
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013405	RHOD GTPase cycle
R-HSA-9013406	RHOQ GTPase cycle
R-HSA-9013409	RHOJ GTPase cycle
R-HSA-9035034	RHOF GTPase cycle
R-HSA-917977	Transferrin endocytosis and recycling
R-HSA-162582	Signal Transduction
R-HSA-194315	Signaling by Rho GTPases
R-HSA-212436	Generic Transcription Pathway
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-382551	Transport of small molecules
R-HSA-5633008	TP53 Regulates Transcription of Cell Death Genes
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-9012999	RHO GTPase cycle
R-HSA-917937	Iron uptake and transport
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 243 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_TRANSITION_METAL_ION_TRANSPORT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_IRON_ION_TRANSPORT, GOBP_COPPER_ION_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GTGCCTT_MIR506, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, GOBP_SECRETION, TURASHVILI_BREAST_DUCTAL_CARCINOMA_VS_DUCTAL_NORMAL_DN, AACTTT_UNKNOWN, PID_P53_DOWNSTREAM_PATHWAY, SENESE_HDAC1_TARGETS_UP, DOUGLAS_BMI1_TARGETS_UP

GO Biological Process (5): iron ion transport (GO:0006826), apoptotic process (GO:0006915), protein secretion (GO:0009306), copper ion import (GO:0015677), monoatomic ion transport (GO:0006811)

GO Molecular Function (8): cupric reductase (NADH) activity (GO:0008823), heme binding (GO:0020037), identical protein binding (GO:0042802), metal ion binding (GO:0046872), ferric-chelate reductase (NADPH) activity (GO:0052851), FAD binding (GO:0071949), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (6): cytoplasm (GO:0005737), endosome (GO:0005768), multivesicular body (GO:0005771), plasma membrane (GO:0005886), endosome membrane (GO:0010008), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
RHO GTPase cycle	5
TP53 Regulates Transcription of Cell Death Genes	1
Iron uptake and transport	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
RNA Polymerase II Transcription	1
Generic Transcription Pathway	1
Transcriptional Regulation by TP53	1
Gene expression (Transcription)	1
Signaling by Rho GTPases	1
Transport of small molecules	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
transition metal ion transport	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
protein transport	1
secretion by cell	1
establishment of protein localization to extracellular region	1
protein localization to extracellular region	1
copper ion transport	1
transport	1
oxidoreductase activity, acting on metal ions, NAD or NADP as acceptor	1
tetrapyrrole binding	1
protein binding	1
cation binding	1
ferric-chelate reductase activity	1
flavin adenine dinucleotide binding	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
endomembrane system	1
cytoplasmic vesicle	1
late endosome	1
membrane	1
cell periphery	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1

Protein interactions and networks

STRING

1172 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STEAP3	PKMYT1	Q99640	908
STEAP3	TPT1	P13693	891
STEAP3	SLC11A2	P49281	804
STEAP3	CYBRD1	Q53TN4	782
STEAP3	BNIP3L	O60238	780
STEAP3	TFRC	P02786	732
STEAP3	SLC40A1	Q9NP59	690
STEAP3	RPS6KB2	Q9UBS0	668
STEAP3	ACO1	P21399	654
STEAP3	TFR2	Q9UP52	644
STEAP3	BNIP3	Q12983	637
STEAP3	FECH	P22830	626
STEAP3	IREB2	P48200	622
STEAP3	FLVCR1	Q9Y5Y0	617
STEAP3	SLC39A14	Q15043	608

IntAct

90 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ASPH	STXBP3	psi-mi:“MI:0914”(association)	0.640
RANBP6	SLC27A2	psi-mi:“MI:0914”(association)	0.640
ENPP6	SCAMP1	psi-mi:“MI:0914”(association)	0.640
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
NRAS	RGL2	psi-mi:“MI:0914”(association)	0.550
STEAP3	TTC21A	psi-mi:“MI:0915”(physical association)	0.530
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
SLC39A4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
DPEP1	ILVBL	psi-mi:“MI:0914”(association)	0.530
MRAP2	GOLIM4	psi-mi:“MI:0914”(association)	0.530
LRRC4C	DVL2	psi-mi:“MI:0914”(association)	0.530
TEX29	TOR1A	psi-mi:“MI:0914”(association)	0.530
FAM177A1	SLC27A2	psi-mi:“MI:0914”(association)	0.530
SCN3B	ABCC5	psi-mi:“MI:0914”(association)	0.530
TIGD5	P4HA2	psi-mi:“MI:0914”(association)	0.530
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
BAD	STEAP3	psi-mi:“MI:0915”(physical association)	0.370
SETD7	STEAP3	psi-mi:“MI:0915”(physical association)	0.370
ACBD3	BCKDHB	psi-mi:“MI:0914”(association)	0.350
	NBAS	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
	FAM171A2	psi-mi:“MI:0914”(association)	0.350
	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
	HLA-C	psi-mi:“MI:0914”(association)	0.350

BioGRID (217): STEAP3 (Affinity Capture-MS), STEAP3 (Affinity Capture-MS), STEAP3 (Affinity Capture-MS), STEAP3 (Affinity Capture-MS), STEAP3 (Affinity Capture-MS), STEAP3 (Affinity Capture-MS), STEAP3 (Affinity Capture-MS), STEAP3 (Affinity Capture-MS), STEAP3 (Proximity Label-MS), STEAP3 (Proximity Label-MS), STEAP3 (Proximity Label-MS), STEAP3 (Affinity Capture-MS), STEAP3 (Affinity Capture-MS), STEAP3 (Affinity Capture-MS), STEAP3 (Affinity Capture-MS)

ESM2 similar proteins: A0A8C2M425, A1A5Z0, A5D6W6, A7YWN2, B0BNG2, B2MVP8, D2HSA6, O19133, O42153, O42154, O75908, O77759, O88908, P35575, P35576, P43428, Q148G2, Q19KA1, Q29RU6, Q4FZU9, Q5E9R1, Q5KR61, Q5RKL5, Q5XK03, Q658P3, Q6AX73, Q6AZ83, Q6GQ62, Q6NSQ9, Q7TPN3, Q7TQM4, Q810K3, Q8BJ52, Q8CI59, Q8IWX5, Q8R1J1, Q8R2R1, Q8WTR4, Q91V79, Q99PR0

Diamond homologs: Q4V8K1, Q5RKL5, Q658P3, Q687X5, Q6NZ63, Q8BWB6, Q8CI59, Q8NFT2, Q923B6, Q9CWR7, Q9GL50, Q9UHE8, O29370

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 126 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
SHC-mediated cascade:FGFR4	5	32.8×	6e-05
FRS-mediated FGFR4 signaling	5	29.9×	6e-05
SHC-mediated cascade:FGFR2	5	28.7×	6e-05
FRS-mediated FGFR2 signaling	5	26.5×	7e-05
Signaling by FGFR2 in disease	5	16.0×	4e-04
RHOQ GTPase cycle	6	13.1×	2e-04
RHOJ GTPase cycle	5	12.1×	1e-03
RHOB GTPase cycle	5	9.3×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
Ras protein signal transduction	7	13.6×	8e-04
transmembrane transport	6	9.5×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	118
Likely benign	33
Benign	16

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
562675	GRCh37/hg19 2q14.1-14.3(chr2:114707932-124328692)x1	Pathogenic

SpliceAI

1196 predictions. Top by Δscore:

Variant	Effect	Δscore
2:119223885:AGAGG:A	donor_loss	1.0000
2:119223886:GAG:G	donor_gain	1.0000
2:119223887:AGG:A	donor_loss	1.0000
2:119223889:G:C	donor_loss	1.0000
2:119245487:A:AG	acceptor_gain	1.0000
2:119245488:G:GC	acceptor_gain	1.0000
2:119245885:C:G	donor_gain	1.0000
2:119247674:CGCA:C	acceptor_loss	1.0000
2:119247675:GCA:G	acceptor_loss	1.0000
2:119247677:A:AG	acceptor_gain	1.0000
2:119247677:AG:A	acceptor_gain	1.0000
2:119247677:AGGT:A	acceptor_gain	1.0000
2:119247678:G:GT	acceptor_gain	1.0000
2:119247678:GG:G	acceptor_gain	1.0000
2:119247678:GGT:G	acceptor_gain	1.0000
2:119247678:GGTG:G	acceptor_gain	1.0000
2:119247678:GGTGC:G	acceptor_gain	1.0000
2:119248202:AGCAG:A	donor_loss	1.0000
2:119248203:GCAG:G	donor_gain	1.0000
2:119248204:CAG:C	donor_loss	1.0000
2:119248205:AG:A	donor_loss	1.0000
2:119248206:GGTAC:G	donor_loss	1.0000
2:119248207:G:A	donor_loss	1.0000
2:119248208:T:G	donor_loss	1.0000
2:119254830:G:GT	donor_gain	1.0000
2:119263054:C:G	acceptor_gain	1.0000
2:119263055:A:AG	acceptor_gain	1.0000
2:119263056:G:GA	acceptor_gain	1.0000
2:119263056:GT:G	acceptor_gain	1.0000
2:119263056:GTC:G	acceptor_gain	1.0000

AlphaMissense

3211 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:119254834:T:C	F391L	0.995
2:119254836:C:A	F391L	0.995
2:119254836:C:G	F391L	0.995
2:119248111:A:C	S309R	0.993
2:119248113:C:A	S309R	0.993
2:119248113:C:G	S309R	0.993
2:119263165:T:C	F432L	0.991
2:119263167:C:A	F432L	0.991
2:119263167:C:G	F432L	0.991
2:119245924:T:A	V143D	0.989
2:119245928:G:C	K144N	0.989
2:119245928:G:T	K144N	0.989
2:119247959:C:A	T258K	0.989
2:119248090:C:A	R302S	0.989
2:119263087:A:C	S406R	0.989
2:119263089:C:A	S406R	0.989
2:119263089:C:G	S406R	0.989
2:119245839:A:C	S115R	0.988
2:119245841:C:A	S115R	0.988
2:119245841:C:G	S115R	0.988
2:119254844:T:A	V394D	0.986
2:119263091:C:A	T407K	0.986
2:119263096:C:G	H409D	0.986
2:119248095:G:C	K303N	0.985
2:119248095:G:T	K303N	0.985
2:119248144:A:C	S320R	0.985
2:119248146:C:A	S320R	0.985
2:119248146:C:G	S320R	0.985
2:119254768:G:C	G369R	0.985
2:119254753:G:A	G364R	0.984

dbSNP variants (sampled 300 via entrez): RS1000150908 (2:119266077 C>T), RS1000247595 (2:119232606 T>C), RS1000356236 (2:119260326 T>C), RS1000444685 (2:119223382 C>T), RS1000616519 (2:119254461 C>T), RS1000705485 (2:119250122 A>G), RS1000770081 (2:119244406 T>G), RS1000918655 (2:119239388 C>T), RS1000977975 (2:119248551 A>G), RS1001011443 (2:119254369 G>A), RS1001028895 (2:119233897 A>G), RS1001093626 (2:119234353 G>A), RS1001193789 (2:119233548 C>G), RS1001247415 (2:119240359 C>A), RS1001304181 (2:119248341 A>G)

Disease associations

OMIM: gene MIM:609671 | disease phenotypes: MIM:615234, MIM:613808

GenCC curated gene-disease

Disease	Classification	Inheritance
severe congenital hypochromic anemia with ringed sideroblasts	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
severe congenital hypochromic anemia with ringed sideroblasts	Disputed	AD

Mondo (2): severe congenital hypochromic anemia with ringed sideroblasts (MONDO:0014094), primary ciliary dyskinesia 15 (MONDO:0013435)

Orphanet (2): Severe congenital hypochromic anemia with ringed sideroblasts (Orphanet:300298), Primary ciliary dyskinesia (Orphanet:244)

HPO phenotypes

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

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000027	Azoospermia
HP:0000135	Hypogonadism
HP:0000821	Hypothyroidism
HP:0000846	Adrenal insufficiency
HP:0000864	Abnormality of the hypothalamus-pituitary axis
HP:0000957	Cafe-au-lait spot
HP:0000980	Pallor
HP:0001433	Hepatosplenomegaly
HP:0001510	Growth delay
HP:0001744	Splenomegaly
HP:0001896	Reticulocytopenia
HP:0001903	Anemia
HP:0001924	Sideroblastic anemia
HP:0002240	Hepatomegaly
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003281	Increased circulating ferritin concentration
HP:0003452	Increased circulating iron concentration
HP:0003593	Infantile onset
HP:0004447	Poikilocytosis
HP:0004823	Anisopoikilocytosis
HP:0011463	Childhood onset
HP:0012134	Dysplastic erythropoesis
HP:0012378	Fatigue
HP:0012463	Elevated transferrin saturation
HP:0012464	Decreased transferrin saturation
HP:0012465	Elevated hepatic iron concentration
HP:0025066	Decreased mean corpuscular volume
HP:0032231	Hypochromia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002142_10	Cocaine dependence	3.000000e-06
GCST008224_1	Renal cell carcinoma x sex interaction	1.000000e-06
GCST010397_64	Gut microbiota (bacterial taxa, rank normal transformation method)	4.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008343	sex interaction measurement
EFO:0007874	gut microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, decreases expression, decreases methylation, increases expression	4
Valproic Acid	affects cotreatment, increases expression	4
sodium arsenite	decreases expression, increases expression	2
cobaltous chloride	decreases expression	2
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Estradiol	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
Tretinoin	decreases expression	2
Aflatoxin B1	decreases methylation	2
TAK-243	decreases sumoylation	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	affects cotreatment, decreases expression	1
sodium arsenate	decreases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
trichostatin A	increases expression	1
hydroxyhydroquinone	decreases expression, decreases reaction	1
beta-lapachone	decreases expression, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
aflatoxin B2	decreases methylation	1
nickel sulfate	increases expression	1
4-aminobenzhydrazide	decreases expression, decreases reaction	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
abrine	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E0Q8	Ubigene HeLa STEAP3 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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