ZSWIM2

Summary

ZSWIM2 (zinc finger SWIM-type containing 2, HGNC:30990) is a protein-coding gene on chromosome 2q32.1, encoding E3 ubiquitin-protein ligase ZSWIM2 (Q8NEG5). E3 ubiquitin-protein ligase involved in the regulation of Fas-, DR3- and DR4-mediated apoptosis.

Predicted to enable ubiquitin protein ligase activity and zinc ion binding activity. Predicted to be involved in apoptotic process and protein polyubiquitination. Predicted to act upstream of or within positive regulation of extrinsic apoptotic signaling pathway via death domain receptors.

Source: NCBI Gene 151112 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 85 total
• MANE Select transcript: NM_182521

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30990
Approved symbol	ZSWIM2
Name	zinc finger SWIM-type containing 2
Location	2q32.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC33890, ZZZ2, MEX
Ensembl gene	ENSG00000163012
Ensembl biotype	protein_coding
Entrez	151112

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 nonsense_mediated_decay

ENST00000295131, ENST00000419862

RefSeq mRNA: 1 — MANE Select: NM_182521 NM_182521

CCDS: CCDS33348

Canonical transcript exons

ENST00000295131 — 9 exons

Exon	Start	End
ENSE00001070635	186827475	186828790
ENSE00001070637	186833946	186834030
ENSE00001070639	186848966	186849170
ENSE00001070640	186833120	186833232
ENSE00001070641	186838959	186839169
ENSE00001070642	186829727	186829880
ENSE00001130202	186837306	186837554
ENSE00001241066	186844717	186844757
ENSE00003506878	186847719	186847795

Expression profiles

Bgee: expression breadth broad, 61 present calls, max score 88.60.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0196 / max 12.6304, expressed in 5 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
32793	0.0128	5
32794	0.0069	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.60	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	66.55	gold quality
left testis	UBERON:0004533	66.49	gold quality
testis	UBERON:0000473	65.92	gold quality
right testis	UBERON:0004534	65.19	gold quality
sperm	CL:0000019	65.12	silver quality
adenohypophysis	UBERON:0002196	56.38	gold quality
pituitary gland	UBERON:0000007	55.59	gold quality
buccal mucosa cell	CL:0002336	54.37	silver quality
lower lobe of lung	UBERON:0008949	50.79	silver quality
prefrontal cortex	UBERON:0000451	48.50	gold quality
cortical plate	UBERON:0005343	48.33	gold quality
Brodmann (1909) area 9	UBERON:0013540	46.22	gold quality
hypothalamus	UBERON:0001898	45.69	gold quality
nucleus accumbens	UBERON:0001882	45.53	gold quality
cardia of stomach	UBERON:0001162	45.46	gold quality
frontal cortex	UBERON:0001870	44.50	gold quality
stromal cell of endometrium	CL:0002255	44.37	gold quality
neocortex	UBERON:0001950	43.85	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
forebrain	UBERON:0001890	43.30	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	42.62	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
cerebral cortex	UBERON:0000956	42.53	gold quality
anterior cingulate cortex	UBERON:0009835	42.24	gold quality
right frontal lobe	UBERON:0002810	41.95	gold quality
vastus lateralis	UBERON:0001379	41.41	gold quality
quadriceps femoris	UBERON:0001377	41.37	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
islet of Langerhans	UBERON:0000006	41.12	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.92

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

36 targeting ZSWIM2, 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-3924	100.00	72.09	2394
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-6073	99.60	70.36	793
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-6080	99.43	69.43	373
HSA-MIR-3140-5P	99.39	69.04	1136
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-5190	99.15	67.76	1234
HSA-MIR-4464	98.95	67.73	820
HSA-MIR-4748	98.95	67.53	810
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-6074	98.89	69.64	2187

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zswim2	ENSDARG00000075700
mus_musculus	Zswim2	ENSMUSG00000034552
rattus_norvegicus	Zswim2	ENSRNOG00000032579

Protein

Protein identifiers

E3 ubiquitin-protein ligase ZSWIM2 — Q8NEG5 (reviewed: Q8NEG5)

Alternative names: MEKK1-related protein X, RING-type E3 ubiquitin transferase ZSWIM2, ZZ-type zinc finger-containing protein 2, Zinc finger SWIM domain-containing protein 2

All UniProt accessions (2): F8WCC6, Q8NEG5

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase involved in the regulation of Fas-, DR3- and DR4-mediated apoptosis. Functions in conjunction with the UBE2D1, UBE2D3 and UBE2E1 E2 ubiquitin-conjugating enzymes.

Subunit / interactions. Dimer. Interacts with UBE2D1.

Tissue specificity. Expression is testis-specific.

Post-translational modifications. Polyubiquitinated. Polyubiquitination is followed by degradation via the proteasome.

Domain organisation. The SWIM-type zinc finger is required for ubiquitination activity.

RefSeq proteins (1): NP_872327* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000433	Znf_ZZ	Domain
IPR001841	Znf_RING	Domain
IPR007527	Znf_SWIM	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR039903	Zswim2	Family
IPR043145	Znf_ZZ_sf	Homologous_superfamily

Pfam: PF00569, PF04434, PF13639

UniProt features (27 total): binding site 8, sequence conflict 7, strand 5, zinc finger region 4, helix 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2DIP	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NEG5-F1	63.82	0.36

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 (8): 261; 267; 270; 234; 237; 249; 252; 258

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 57 (showing top): GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_REGULATION_OF_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_VIA_DEATH_DOMAIN_RECEPTORS, GOBP_APOPTOTIC_SIGNALING_PATHWAY, GOBP_REGULATION_OF_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_VIA_DEATH_DOMAIN_RECEPTORS, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEIN_POLYUBIQUITINATION, MYB_Q3, GOBP_POSITIVE_REGULATION_OF_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_VIA_DEATH_DOMAIN_RECEPTORS, GOBP_POSITIVE_REGULATION_OF_APOPTOTIC_SIGNALING_PATHWAY, MYB_Q5_01, GOBP_REGULATION_OF_APOPTOTIC_SIGNALING_PATHWAY, GOMF_ACYLTRANSFERASE_ACTIVITY, GOMF_AMINOACYLTRANSFERASE_ACTIVITY

GO Biological Process (3): protein polyubiquitination (GO:0000209), apoptotic process (GO:0006915), positive regulation of extrinsic apoptotic signaling pathway via death domain receptors (GO:1902043)

GO Molecular Function (5): zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), ubiquitin-protein transferase activity (GO:0004842), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
extrinsic apoptotic signaling pathway via death domain receptors	1
regulation of extrinsic apoptotic signaling pathway via death domain receptors	1
positive regulation of extrinsic apoptotic signaling pathway	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
ubiquitin-like protein transferase activity	1
catalytic activity	1
cation binding	1

Protein interactions and networks

STRING

508 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZSWIM2	TSNAXIP1	Q2TAA8	563
ZSWIM2	RSPH14	Q9UHP6	535
ZSWIM2	OXNAD1	Q96HP4	534
ZSWIM2	CCDC146	Q8IYE0	517
ZSWIM2	CFAP74	Q9C0B2	500
ZSWIM2	RSPH10B	P0C881	497
ZSWIM2	CFAP52	Q8N1V2	466
ZSWIM2	ZZZ3	Q8IYH5	458
ZSWIM2	LRRC34	Q8IZ02	457
ZSWIM2	EBNA1BP2	Q99848	457
ZSWIM2	LRRC23	Q53EV4	453
ZSWIM2	SLC66A1	Q6ZP29	451
ZSWIM2	CFAP161	Q6P656	449
ZSWIM2	SAXO2	Q658L1	425
ZSWIM2	CFAP57	Q96MR6	425

IntAct

7 interactions, top by confidence:

A	B	Type	Score
ZSWIM2	SEMG1	psi-mi:“MI:0914”(association)	0.530
ZSWIM2	EZR	psi-mi:“MI:0915”(physical association)	0.400
ZSWIM2	UBE2U	psi-mi:“MI:0915”(physical association)	0.370
ECE1	ZSWIM2	psi-mi:“MI:0915”(physical association)	0.370
MAGEA11	ZSWIM2	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (17): ZSWIM2 (Two-hybrid), BCAM (Affinity Capture-MS), TKTL2 (Affinity Capture-MS), SEMG1 (Affinity Capture-MS), LRFN4 (Affinity Capture-MS), RNASE7 (Affinity Capture-MS), ZSWIM2 (Synthetic Lethality), ZSWIM2 (Proximity Label-MS), TKTL2 (Affinity Capture-MS), LRFN4 (Affinity Capture-MS), BCAM (Affinity Capture-MS), RNASE7 (Affinity Capture-MS), SEMG1 (Affinity Capture-MS), ZSWIM2 (Positive Genetic), ZSWIM2 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A1L8HU22, C0SV12, C0SVM5, F4I443, O22199, O22800, O23379, O50055, O65312, O82256, O82617, P0CB22, Q0IGM7, Q0P4S5, Q1G3I2, Q1G3Q4, Q39057, Q6EU49, Q6NPP4, Q6NQ79, Q6ZJM9, Q8BZ05, Q8GZ42, Q8NEG5, Q8WZ64, Q940T9, Q946J2, Q96288, Q96502, Q9C5X4, Q9C7E8, Q9C9F4, Q9D9X6, Q9FHH8, Q9FNC7, Q9FZ36, Q9LDT3, Q9LJ44, Q9LRM4, Q9LUA9

Diamond homologs: A2CI97, A2CI98, A2CJ06, G3V7L1, O97592, P11530, P11531, P11532, P11533, P46939, Q05AA6, Q0KI50, Q13474, Q5GN48, Q7YU29, Q8NEG5, Q9EPA0, Q9TW65, Q9VDW3, Q9VDW6, Q9Y4J8, A5WWA0, E9QAU8, F4HZZ4, F4HZZ5, F4I2Y3, O22755, O43567, O64762, O82353, P0C034, P0DPR2, P87119, Q07G42, Q08CG8, Q08D68, Q08DI6, Q0II22, Q0V9R0, Q0VD51

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	ZSWIM2	ubiquitination
UBE2D1	“up-regulates activity”	ZSWIM2	binding
UBE2E1	“up-regulates activity”	ZSWIM2	binding
ZSWIM2	up-regulates	Apoptosis
UBE2D3	“up-regulates activity”	ZSWIM2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	77
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1138 predictions. Top by Δscore:

Variant	Effect	Δscore
2:186829876:CTTGG:C	acceptor_gain	1.0000
2:186833118:AC:A	donor_gain	1.0000
2:186833119:CC:C	donor_gain	1.0000
2:186837304:A:AC	donor_gain	1.0000
2:186837305:C:CT	donor_gain	1.0000
2:186837317:C:A	donor_gain	1.0000
2:186839167:CAG:C	acceptor_gain	1.0000
2:186839170:C:CC	acceptor_gain	1.0000
2:186848964:A:AC	donor_gain	1.0000
2:186848965:C:CC	donor_gain	1.0000
2:186848965:CT:C	donor_gain	1.0000
2:186828791:C:CC	acceptor_gain	0.9900
2:186828792:T:C	acceptor_gain	0.9900
2:186829881:C:CC	acceptor_gain	0.9900
2:186837316:T:TA	donor_gain	0.9900
2:186837344:A:AC	donor_gain	0.9900
2:186838954:ATCAC:A	donor_loss	0.9900
2:186838955:TCA:T	donor_loss	0.9900
2:186838956:CAC:C	donor_loss	0.9900
2:186838957:A:T	donor_loss	0.9900
2:186839165:AGCAG:A	acceptor_gain	0.9900
2:186839166:GCAG:G	acceptor_gain	0.9900
2:186839167:CAGC:C	acceptor_gain	0.9900
2:186839168:AG:A	acceptor_gain	0.9900
2:186839169:GCTAG:G	acceptor_loss	0.9900
2:186839171:T:G	acceptor_loss	0.9900
2:186847712:CACT:C	donor_loss	0.9900
2:186847716:T:TC	donor_loss	0.9900
2:186847717:A:AC	donor_gain	0.9900
2:186847718:C:CC	donor_gain	0.9900

AlphaMissense

4208 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:186837469:A:G	C194R	0.991
2:186839014:A:G	C147R	0.986
2:186828788:A:C	F366L	0.985
2:186828788:A:T	F366L	0.985
2:186828790:A:G	F366L	0.985
2:186838963:A:G	C164R	0.984
2:186829792:A:G	C344R	0.983
2:186833950:C:G	R275P	0.981
2:186837523:A:G	C176R	0.981
2:186837468:C:G	C194S	0.980
2:186837469:A:T	C194S	0.980
2:186849005:G:C	F42L	0.980
2:186849005:G:T	F42L	0.980
2:186849007:A:G	F42L	0.980
2:186829791:C:G	C344S	0.979
2:186829792:A:T	C344S	0.979
2:186837349:A:G	C234R	0.978
2:186838962:C:G	C164S	0.976
2:186838963:A:T	C164S	0.976
2:186839012:G:C	C147W	0.976
2:186837522:C:G	C176S	0.975
2:186837523:A:T	C176S	0.975
2:186839005:A:G	C150R	0.975
2:186833217:A:G	W282R	0.974
2:186833217:A:T	W282R	0.974
2:186838961:G:C	C164W	0.973
2:186828742:A:G	C382R	0.972
2:186837446:A:C	F201L	0.971
2:186837446:A:T	F201L	0.971
2:186837448:A:G	F201L	0.971

dbSNP variants (sampled 300 via entrez): RS1000003166 (2:186849048 C>G), RS1000303248 (2:186830264 C>T), RS1000353435 (2:186830117 G>A,T), RS1000579638 (2:186850313 A>C), RS1000729022 (2:186831203 T>C), RS1000739157 (2:186828767 G>A), RS1000900157 (2:186834382 G>A), RS1001000816 (2:186840657 A>T), RS1001045485 (2:186840352 A>G), RS1001088173 (2:186829063 T>C), RS1001230098 (2:186832965 C>A,G,T), RS1001283041 (2:186834398 G>T), RS1001335669 (2:186834617 C>A), RS1001552861 (2:186846016 T>G), RS1001581002 (2:186840856 T>C,G)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST006624_75	Systolic blood pressure	1.000000e-11
GCST90020025_1718	Waist-to-hip ratio adjusted for BMI	3.000000e-08
GCST90020026_371	Hip index	2.000000e-09
GCST90020029_844	Waist circumference adjusted for body mass index	4.000000e-08
GCST90020029_845	Waist circumference adjusted for body mass index	1.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
CGP 52608	affects binding, increases reaction	1
semilicoisoflavone B	decreases phosphorylation	1
Arsenic	increases methylation	1
Benzo(a)pyrene	increases methylation	1
Lead	affects methylation	1
Tobacco Smoke Pollution	decreases expression	1

Clinical trials (associated diseases)

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