ZRANB3

Summary

ZRANB3 (zinc finger RANBP2-type containing 3, HGNC:25249) is a protein-coding gene on chromosome 2q21.3, encoding DNA annealing helicase and endonuclease ZRANB3 (Q5FWF4). DNA annealing helicase and endonuclease required to maintain genome stability at stalled or collapsed replication forks by facilitating fork restart and limiting inappropriate recombination that could occur during template switching events.

Enables ATP-dependent DNA/DNA annealing activity; DNA endonuclease activity; and K63-linked polyubiquitin modification-dependent protein binding activity. Involved in DNA repair; replication fork reversal; and response to UV. Located in nuclear replication fork and nucleoplasm.

Source: NCBI Gene 84083 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 185 total
• MANE Select transcript: NM_032143

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25249
Approved symbol	ZRANB3
Name	zinc finger RANBP2-type containing 3
Location	2q21.3
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP434B1727, AH2
Ensembl gene	ENSG00000121988
Ensembl biotype	protein_coding
OMIM	615655
Entrez	84083

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 14 protein_coding, 3 protein_coding_CDS_not_defined, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000264159, ENST00000401392, ENST00000403017, ENST00000412849, ENST00000452187, ENST00000472452, ENST00000474919, ENST00000492193, ENST00000495945, ENST00000536680, ENST00000619650, ENST00000907299, ENST00000907300, ENST00000907301, ENST00000907302, ENST00000907303, ENST00000907304, ENST00000907305, ENST00000923651, ENST00000923652, ENST00000957670

RefSeq mRNA: 3 — MANE Select: NM_032143 NM_001286568, NM_001286569, NM_032143

CCDS: CCDS46419, CCDS67963, CCDS74580

Canonical transcript exons

ENST00000264159 — 21 exons

Exon	Start	End
ENSE00001468503	135531127	135531218
ENSE00001559609	135196969	135200440
ENSE00002529378	135227812	135228015
ENSE00003465727	135390802	135390820
ENSE00003475041	135219077	135219178
ENSE00003481137	135230513	135230927
ENSE00003483209	135271768	135271887
ENSE00003488862	135353450	135353628
ENSE00003524031	135224426	135224517
ENSE00003525711	135265534	135265686
ENSE00003528472	135315359	135315530
ENSE00003531216	135345550	135345635
ENSE00003550325	135208868	135208978
ENSE00003633442	135217465	135217607
ENSE00003641465	135313489	135313605
ENSE00003647240	135202832	135202963
ENSE00003649034	135275636	135275755
ENSE00003660865	135349984	135350215
ENSE00003682075	135504329	135504496
ENSE00003692473	135207434	135207836
ENSE00003726372	135268962	135269141

Expression profiles

Bgee: expression breadth ubiquitous, 198 present calls, max score 86.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.3526 / max 169.1686, expressed in 1568 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
30764	4.7296	1443
30763	1.6099	925
30765	0.0131	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.33	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.40	gold quality
pancreatic ductal cell	CL:0002079	83.47	gold quality
adrenal tissue	UBERON:0018303	79.85	gold quality
cardiac muscle of right atrium	UBERON:0003379	77.63	gold quality
left ventricle myocardium	UBERON:0006566	77.57	gold quality
calcaneal tendon	UBERON:0003701	77.39	gold quality
tibialis anterior	UBERON:0001385	77.35	silver quality
sural nerve	UBERON:0015488	77.22	gold quality
ventricular zone	UBERON:0003053	76.73	gold quality
kidney epithelium	UBERON:0004819	75.53	gold quality
stromal cell of endometrium	CL:0002255	75.39	gold quality
bone marrow cell	CL:0002092	75.16	gold quality
deltoid	UBERON:0001476	74.72	silver quality
corpus callosum	UBERON:0002336	74.26	gold quality
islet of Langerhans	UBERON:0000006	73.32	gold quality
ganglionic eminence	UBERON:0004023	72.81	gold quality
gastrocnemius	UBERON:0001388	72.56	gold quality
epithelial cell of pancreas	CL:0000083	72.53	silver quality
muscle of leg	UBERON:0001383	72.41	gold quality
buccal mucosa cell	CL:0002336	72.32	gold quality
bone marrow	UBERON:0002371	72.13	gold quality
skeletal muscle organ	UBERON:0014892	72.03	gold quality
hindlimb stylopod muscle	UBERON:0004252	71.85	gold quality
colonic epithelium	UBERON:0000397	71.78	gold quality
pancreas	UBERON:0001264	71.75	gold quality
right lobe of liver	UBERON:0001114	71.56	gold quality
body of pancreas	UBERON:0001150	71.47	gold quality
muscle tissue	UBERON:0002385	71.13	gold quality
right adrenal gland cortex	UBERON:0035827	71.11	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.44

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

95 targeting ZRANB3, 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-4668-3P	100.00	68.74	2635
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481

Literature-anchored findings (GeneRIF, showing 13)

• structural and functional differences between AH2 and HARP suggest that different annealing helicases have distinct functions in the cell. (PMID:21078962)
• ZRANB3 translocase, a SNF2 family member related to the SIOD disorder SMARCAL1 protein, is recruited by polyubiquitinated PCNA to promote fork restart following replication arrest. (PMID:22704558)
• AH2 is recruited to stalled replication forks and that cells depleted of AH2 are hypersensitive to replication stresses. (PMID:22705370)
• a role for ZRANB3 in the replication stress response and suggest new insights into how DNA repair is coordinated with DNA replication to maintain genome stability. (PMID:22759634)
• Here is described a substrate recognition domain within ZRANB3 that is needed for it to recognize forked DNA structures, hydrolyze ATP, catalyze fork remodeling, and act as a structure-specific endonuclease. (PMID:26884333)
• PCNA and ATP-dependency serve as a multi-layered regulatory mechanism that modulates ZRANB3 activity at replication forks. (PMID:28621305)
• Damage-induced fork reversal in mammalian cells requires PCNA ubiquitination, UBC13, and K63-linked polyubiquitin chains, previously involved in error-free damage tolerance. Fork reversal in vivo also requires ZRANB3 translocase activity and its interaction with polyubiquitinated PCNA, pinpointing ZRANB3 as a key effector of error-free DNA damage tolerance. (PMID:28886337)
• A large number of SNF2 family, DNA and ATP-dependent motor proteins are needed during transcription, DNA replication, and DNA repair to manipulate protein-DNA interactions and change DNA structure. SMARCAL1, ZRANB3, and HLTF are three related members of this family with specialized functions that maintain genome stability during DNA replication. [review] (PMID:28954549)
• depletion of SMARCAL1, a SNF2-family DNA translocase that remodels stalled forks, restores replication fork stability and reduces the formation of replication stress-induced DNA breaks and chromosomal aberrations in BRCA1/2-deficient cells. In addition to SMARCAL1, other SNF2-family fork remodelers, including ZRANB3 and HLTF, cause nascent DNA degradation and genomic instability (PMID:29053959)
• Nuclear RNR-alpha antagonizes cell proliferation by directly inhibiting ZRANB3 (PMID:30150681)
• ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response. (PMID:31324766)
• Time for remodeling: SNF2-family DNA translocases in replication fork metabolism and human disease. (PMID:32971328)
• RFWD3 promotes ZRANB3 recruitment to regulate the remodeling of stalled replication forks. (PMID:37036693)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zranb3	ENSDARG00000091538
mus_musculus	Zranb3	ENSMUSG00000036086
rattus_norvegicus	Zranb3	ENSRNOG00000003979

Paralogs (30): HLTF (ENSG00000071794), SMARCA2 (ENSG00000080503), SRCAP (ENSG00000080603), ATRX (ENSG00000085224), RAD54L (ENSG00000085999), BTAF1 (ENSG00000095564), CHD8 (ENSG00000100888), SMARCA1 (ENSG00000102038), CHD4 (ENSG00000111642), CHD5 (ENSG00000116254), TTF2 (ENSG00000116830), HELLS (ENSG00000119969), CHD6 (ENSG00000124177), SMARCA4 (ENSG00000127616), INO80 (ENSG00000128908), CHD1L (ENSG00000131778), SMARCAL1 (ENSG00000138375), SHPRH (ENSG00000146414), SMARCA5 (ENSG00000153147), CHD1 (ENSG00000153922), SMARCAD1 (ENSG00000163104), RAD54L2 (ENSG00000164080), CHD3 (ENSG00000170004), CHD7 (ENSG00000171316), CHD2 (ENSG00000173575), CHD9 (ENSG00000177200), EP400 (ENSG00000183495), ERCC6L (ENSG00000186871), RAD54B (ENSG00000197275), ERCC6 (ENSG00000225830)

Protein

Protein identifiers

DNA annealing helicase and endonuclease ZRANB3 — Q5FWF4 (reviewed: Q5FWF4)

Alternative names: Annealing helicase 2, Zinc finger Ran-binding domain-containing protein 3

All UniProt accessions (3): Q5FWF4, F5GYN7, F8WCT9

UniProt curated annotations — full annotation on UniProt →

Function. DNA annealing helicase and endonuclease required to maintain genome stability at stalled or collapsed replication forks by facilitating fork restart and limiting inappropriate recombination that could occur during template switching events. Recruited to the sites of stalled DNA replication by polyubiquitinated PCNA and acts as a structure-specific endonuclease that cleaves the replication fork D-loop intermediate, generating an accessible 3’-OH group in the template of the leading strand, which is amenable to extension by DNA polymerase. In addition to endonuclease activity, also catalyzes the fork regression via annealing helicase activity in order to prevent disintegration of the replication fork and the formation of double-strand breaks.

Subunit / interactions. Interacts (via PIP-box, APIM motif and RanBP2-type zinc finger) with PCNA (when PCNA is polyubiquitinated via ‘Lys-63’-linked polyubiquitin); the interaction stimulates ZRANB3 endonuclease activity and is required for ZRANB3 recruitment to DNA replication sites.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. (Microbial infection) Methylation at Cys-630 by enteropathogenic E.coli protein NleE or S.flexneri protein OspZ: methylation disrupts ability to bind ‘Lys-63’-linked ubiquitin.

Domain organisation. The PIP-box and APIM motif mediate the interaction with PCNA, while the RanBP2-type zinc finger mediates binding to ‘Lys-63’-linked polyubiquitin.

Miscellaneous. In contrast to classical helicases that unwing DNA, annealing helicases rewind it.

Similarity. Belongs to the SNF2/RAD54 helicase family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q5FWF4-1	1	yes
Q5FWF4-2	2
Q5FWF4-3	3
Q5FWF4-4	4
Q5FWF4-5	5

RefSeq proteins (3): NP_001273497, NP_001273498, NP_115519* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000330	SNF2_N	Domain
IPR001650	Helicase_C-like	Domain
IPR001876	Znf_RanBP2	Domain
IPR002711	HNH	Domain
IPR003615	HNH_nuc	Domain
IPR014001	Helicase_ATP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036443	Znf_RanBP2_sf	Homologous_superfamily
IPR038718	SNF2-like_sf	Homologous_superfamily
IPR049730	SNF2/RAD54-like_C	Domain

Pfam: PF00176, PF00271, PF00641, PF01844

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (80 total): mutagenesis site 32, helix 10, splice variant 7, binding site 5, region of interest 4, domain 3, short sequence motif 3, compositionally biased region 3, sequence variant 3, sequence conflict 3, modified residue 2, strand 2, chain 1, zinc finger region 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
5MLO	X-RAY DIFFRACTION	1.96
5MKW	X-RAY DIFFRACTION	2
5YD8	X-RAY DIFFRACTION	2.3
5MLW	X-RAY DIFFRACTION	2.45

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5FWF4-F1	72.76	0.30

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 (5): 59–66; 965; 968; 1041; 1044

Post-translational modifications (2): 569, 630

Mutagenesis-validated functional residues (32):

Position	Phenotype
65	abolishes atpase activity. abolishes endonuclease activity. abolishes endonuclease activity; when associated with a-1021
66	almost abolishes atpase acitivity.
157–158	abolishes fork regression activity.
163	loss of dna-dependent atpase activity.
169	abolishes atpase acitivity. abolishes endonuclease activity.
401	reduces atpase acitivity. abolishes endonuclease activity.
519	abolishes interaction with pcna; when associated with a-522; 525-a-a-526 and a-1075. abolishes interaction with pcna; wh
522	abolishes interaction with pcna; when associated with a-519; 525-a-a-526 and a-1075.
525–526	abolishes interaction with pcna; when associated with a-519; a-522 and a-1075.
525	abolishes interaction with pcna; when associated with a-519.
625	abolishes interaction with ’lys-63’-linked polyubiquitin.
631–632	abolishes interaction with ’lys-63’-linked polyubiquitin.
631	impaired interaction with ’lys-63’-linked polyubiquitin.
632	abolishes interaction with ’lys-63’-linked polyubiquitin.
634	abolishes interaction with ’lys-63’-linked polyubiquitin.
643	impaired interaction with polyubiquitin.
762–764	loss of dna-binding, dna-dependent atpase and nuclease activities.
792–794	loss of dna-dependent atpase activity.
947	reduces atpase acitivity. reduces endonuclease activity.
984	no effect on atpase activity. no effect on endonuclease activity.
987	reduces atpase activity. reduces endonuclease activity.
988	no effect on atpase activity. no effect on endonuclease activity.
998	no effect on atpase activity. no effect on endonuclease activity.
1009	reduces atpase activity. strongly reduces endonuclease activity.
1015	no effect on atpase acitivity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 141 (showing top): GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_NUCLEASE_ACTIVITY, GOCC_NUCLEAR_REPLICATION_FORK, KONDO_COLON_CANCER_HCP_WITH_H3K27ME1, GOBP_RESPONSE_TO_UV, GOBP_DNA_DAMAGE_RESPONSE, GOBP_RESPONSE_TO_RADIATION, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, FISCHER_DREAM_TARGETS, IVANOVA_HEMATOPOIESIS_EARLY_PROGENITOR, GOBP_DNA_REPLICATION, GOBP_RESPONSE_TO_LIGHT_STIMULUS, GOMF_DNA_ENDONUCLEASE_ACTIVITY, GOMF_SINGLE_STRANDED_DNA_BINDING

GO Biological Process (5): DNA repair (GO:0006281), DNA damage response (GO:0006974), response to UV (GO:0009411), replication fork processing (GO:0031297), replication fork reversal (GO:0071932)

GO Molecular Function (14): helicase activity (GO:0004386), DNA endonuclease activity (GO:0004520), ATP binding (GO:0005524), zinc ion binding (GO:0008270), hydrolase activity (GO:0016787), ATP-dependent DNA/DNA annealing activity (GO:0036310), K63-linked polyubiquitin modification-dependent protein binding (GO:0070530), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), catalytic activity (GO:0003824), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): nucleoplasm (GO:0005654), nuclear replication fork (GO:0043596), nucleus (GO:0005634), chromosome (GO:0005694)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catalytic activity, acting on a nucleic acid	2
binding	2
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
response to light stimulus	1
DNA-templated DNA replication maintenance of fidelity	1
replication fork processing	1
nucleic acid conformation isomerase activity	1
ATP-dependent activity	1
endonuclease activity	1
DNA nuclease activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion binding	1
catalytic activity	1
ATP-dependent activity, acting on DNA	1
DNA/DNA annealing activity	1
polyubiquitin modification-dependent protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
nuclease activity	1
cation binding	1
nuclear lumen	1
cellular anatomical structure	1
nuclear chromosome	1
nucleus	1
replication fork	1
CMG complex	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

2199 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZRANB3	RAD51	Q06609	748
ZRANB3	FBH1	Q8NFZ0	731
ZRANB3	RADX	Q6NSI4	725
ZRANB3	PRIMPOL	Q96LW4	708
ZRANB3	FANCM	Q8IYD8	707
ZRANB3	MUS81	Q96NY9	704
ZRANB3	DNA2	P51530	679
ZRANB3	WRN	Q14191	678
ZRANB3	WRNIP1	Q96S55	658
ZRANB3	RECQL	P46063	645
ZRANB3	HLTF	Q14527	620
ZRANB3	BRCA2	P51587	616
ZRANB3	BOD1L1	Q8NFC6	602
ZRANB3	EXO1	Q9UQ84	591
ZRANB3	RECQL5	O94762	586

IntAct

36 interactions, top by confidence:

A	B	Type	Score
KPNA4	MYC	psi-mi:“MI:0915”(physical association)	0.780
ZRANB3	PCNA	psi-mi:“MI:0914”(association)	0.600
ZRANB3	PCNA	psi-mi:“MI:0403”(colocalization)	0.600
ZRANB3	PCNA	psi-mi:“MI:0915”(physical association)	0.600
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
TPCN2	AP3B1	psi-mi:“MI:0914”(association)	0.530
ISLR	BCKDK	psi-mi:“MI:0914”(association)	0.530
IMPDH1	BCAT2	psi-mi:“MI:0914”(association)	0.530
H3C13	ZRANB3	psi-mi:“MI:0915”(physical association)	0.400
ZRANB3	MCM3	psi-mi:“MI:0914”(association)	0.350
CUL2	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
RAMP2	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CTLA4	TMEM120B	psi-mi:“MI:0914”(association)	0.350
PIPSL	C1orf226	psi-mi:“MI:0914”(association)	0.350
FTL	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350
PTGES3	SBNO1	psi-mi:“MI:0914”(association)	0.350
DNAJA2	DENND11	psi-mi:“MI:0914”(association)	0.350
MGARP	RTL8C	psi-mi:“MI:0914”(association)	0.350
TIGIT	FAM171A2	psi-mi:“MI:0914”(association)	0.350
FGF12	SUPT5H	psi-mi:“MI:0914”(association)	0.350
CD79B	GOLIM4	psi-mi:“MI:0914”(association)	0.350
CAMK2D	SETD1A	psi-mi:“MI:0914”(association)	0.350

BioGRID (43): ZRANB3 (Affinity Capture-MS), ZRANB3 (Affinity Capture-MS), ZRANB3 (Affinity Capture-MS), ZRANB3 (Affinity Capture-MS), ZRANB3 (Affinity Capture-MS), ZRANB3 (Affinity Capture-MS), ZRANB3 (Affinity Capture-MS), ZRANB3 (Affinity Capture-MS), ZRANB3 (Affinity Capture-RNA), ZRANB3 (Proximity Label-MS), ZRANB3 (Proximity Label-MS), ZRANB3 (Affinity Capture-MS), ZRANB3 (Affinity Capture-MS), ZRANB3 (Affinity Capture-MS), ZRANB3 (Affinity Capture-MS)

ESM2 similar proteins: A0A1P8ASY1, A1L2E4, A3KMI0, A4IHT0, A4QNL8, B1H2Q2, C5DXG0, E1BB03, E7BQV0, F4I9Q5, F4J2K2, F4KH86, H9JD76, O16810, O23461, P45951, Q09499, Q0D622, Q0KHV6, Q0P4U8, Q0PCS3, Q10107, Q26261, Q498E7, Q4R8E0, Q4V8V2, Q566V3, Q58DC8, Q5FWF4, Q5U595, Q682U6, Q6AZT2, Q6DDU8, Q6NW58, Q6P158, Q6P5D3, Q7XIT1, Q84JF4, Q8GY88, Q94C95

Diamond homologs: A2BGR3, A3KMX0, A4PBL4, A4R227, A6QQR4, A6ZU34, A7EQA8, A7TJI3, A7Z019, B6ZLK2, C0H4W3, E1BB03, E7F1C4, E9PZM4, F1Q8K0, F4I2H2, F4IHS2, F4IV99, F4J9M5, F8VPZ5, O12944, O14646, O14647, O60264, P0CO16, P0CO17, P28370, P31380, P32333, P32849, P36607, P38144, P40201, P40352, P41410, P41877, P43610, P51531, P51532, P53115

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	139
Likely benign	11
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

6082 predictions. Top by Δscore:

Variant	Effect	Δscore
2:135150364:CACAG:C	acceptor_loss	1.0000
2:135150366:CA:C	acceptor_loss	1.0000
2:135150367:A:AG	acceptor_gain	1.0000
2:135150367:A:C	acceptor_loss	1.0000
2:135150367:AG:A	acceptor_gain	1.0000
2:135150368:G:GG	acceptor_gain	1.0000
2:135150368:GG:G	acceptor_gain	1.0000
2:135150490:A:G	donor_gain	1.0000
2:135150502:TTAAG:T	donor_loss	1.0000
2:135150503:TAAG:T	donor_loss	1.0000
2:135150504:AAGGT:A	donor_loss	1.0000
2:135150507:GTGG:G	donor_loss	1.0000
2:135150508:T:A	donor_loss	1.0000
2:135153647:A:AG	acceptor_gain	1.0000
2:135153647:AG:A	acceptor_gain	1.0000
2:135153648:G:GT	acceptor_gain	1.0000
2:135153648:GG:G	acceptor_gain	1.0000
2:135153648:GGC:G	acceptor_gain	1.0000
2:135153648:GGCA:G	acceptor_gain	1.0000
2:135153865:G:T	donor_gain	1.0000
2:135153874:AAG:A	donor_loss	1.0000
2:135153875:AGGTA:A	donor_loss	1.0000
2:135153876:GG:G	donor_loss	1.0000
2:135162645:G:GT	donor_gain	1.0000
2:135162647:AGAAG:A	donor_loss	1.0000
2:135162649:AAGGT:A	donor_loss	1.0000
2:135162650:AGGTA:A	donor_loss	1.0000
2:135162651:GGTAA:G	donor_loss	1.0000
2:135162652:G:GA	donor_loss	1.0000
2:135162653:T:A	donor_loss	1.0000

AlphaMissense

7140 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:135269059:C:G	R430P	0.999
2:135271796:G:T	A393D	0.999
2:135350018:A:G	L186P	0.999
2:135350102:T:A	E158V	0.999
2:135353529:A:G	W94R	0.999
2:135353529:A:T	W94R	0.999
2:135353604:C:G	A69P	0.999
2:135353616:T:G	K65Q	0.999
2:135353618:C:A	G64V	0.999
2:135353618:C:T	G64E	0.999
2:135504367:C:A	Q41H	0.999
2:135504367:C:G	Q41H	0.999
2:135269049:T:A	R433S	0.998
2:135269049:T:G	R433S	0.998
2:135269050:C:G	R433T	0.998
2:135269069:C:G	A427P	0.998
2:135269141:C:G	G403R	0.998
2:135269141:C:T	G403R	0.998
2:135271775:G:T	A400D	0.998
2:135271786:G:C	S396R	0.998
2:135271786:G:T	S396R	0.998
2:135271788:T:G	S396R	0.998
2:135271790:A:G	L395P	0.998
2:135271823:A:G	F384S	0.998
2:135271871:A:T	I368K	0.998
2:135315440:T:A	R256S	0.998
2:135315440:T:G	R256S	0.998
2:135315441:C:G	R256T	0.998
2:135345634:A:G	L198P	0.998
2:135350102:T:G	E158A	0.998

dbSNP variants (sampled 300 via entrez): RS1000018094 (2:135300261 T>A,G), RS1000025079 (2:135243662 A>G), RS1000051349 (2:135393546 A>C), RS1000058026 (2:135423720 CA>C), RS1000059569 (2:135450552 G>A,C), RS1000060847 (2:135403702 G>A,C,T), RS1000062384 (2:135210931 A>G,T), RS1000069015 (2:135291514 A>G), RS1000083540 (2:135393843 G>A), RS1000083726 (2:135503907 T>C), RS1000084784 (2:135531610 GCCT>G,GCCTCCT), RS1000110884 (2:135414575 G>A), RS1000134775 (2:135307133 C>T), RS1000139260 (2:135273455 C>A), RS1000140100 (2:135456959 T>A,C)

Disease associations

OMIM: gene MIM:615655 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST004066_138	Hip circumference	2.000000e-06
GCST004066_72	Hip circumference	6.000000e-09
GCST004863_60	Mosquito bite size	2.000000e-09
GCST005951_43	Body mass index	5.000000e-09
GCST005951_44	Body mass index	1.000000e-09
GCST008161_115	Waist circumference adjusted for body mass index	8.000000e-06
GCST008463_1	Type 2 diabetes	7.000000e-09
GCST010204_191	Low density lipoprotein cholesterol levels	4.000000e-12

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0008378	mosquito bite reaction size measurement
EFO:0004340	body mass index
EFO:0007789	BMI-adjusted waist circumference
EFO:0004611	low density lipoprotein cholesterol measurement

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
Valproic Acid	affects cotreatment, decreases expression, affects expression	7
Benzo(a)pyrene	decreases expression	3
Aflatoxin B1	affects expression, decreases expression	3
Cisplatin	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
coumarin	decreases phosphorylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	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	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Panobinostat	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Caffeine	decreases phosphorylation	1
Dexamethasone	increases expression, affects cotreatment	1
Dimethyl Sulfoxide	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Indomethacin	increases expression, affects cotreatment	1
Methyl Methanesulfonate	decreases expression	1
N-Nitrosopyrrolidine	decreases expression	1

Clinical trials (associated diseases)

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