IZUMO2

Summary

IZUMO2 (IZUMO family member 2, HGNC:28518) is a protein-coding gene on chromosome 19q13.33, encoding Izumo sperm-egg fusion protein 2 (Q6UXV1).

Predicted to be located in membrane.

Source: NCBI Gene 126123 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• Clinical variants (ClinVar): 41 total
• GTEx eGene: eQTL in 8 tissues, sQTL in 0 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.25 (unconstrained)
• MANE Select transcript: NM_152358

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28518
Approved symbol	IZUMO2
Name	IZUMO family member 2
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	MGC33947, SCRL
Ensembl gene	ENSG00000161652
Ensembl biotype	protein_coding
OMIM	618895
Entrez	126123

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 2 nonsense_mediated_decay

MANE Select: ENST00000293405

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 5: 2

ENST00000293405, ENST00000486050, ENST00000594854, ENST00000600293, ENST00000916628, ENST00001069830, ENST00001131015, ENST00001143366

RefSeq mRNA: 2 — MANE Select: NM_152358 NM_001321449, NM_152358

CCDS: CCDS12792

Canonical transcript exons

ENST00000293405 — 7 exons

Exon	Start	End
ENSE00001059493	50162739	50162813
ENSE00001751544	50152548	50152651
ENSE00001918580	50162963	50163281
ENSE00003559386	50158268	50158348
ENSE00003578361	50154600	50154726
ENSE00003672786	50159230	50159250
ENSE00003676949	50159494	50159580

Expression profiles

Bgee: expression breadth broad, 82 present calls, max score 93.99.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0909 / max 38.7933, expressed in 38 samples.

Highest expression (Bgee): testis, sperm, male germ line stem cell (sensu Vertebrata) in testis, adult organism, primordial germ cell in gonad.

Genetic regulation across tissues (GTEx eQTL / sQTL)

IZUMO2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 8 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

8 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	eqtl	9.1e-13	-0.49	19:50163132:G:A
Testis	eqtl	3.3e-07	-0.16	19:50163132:G:A
Brain Nucleus accumbens basal ganglia	eqtl	8.0e-07	-0.64	19:50163132:G:A
Skin Sun Exposed Lower leg	eqtl	5.9e-06	+0.29	19:50215439:C:G
Brain Caudate basal ganglia	eqtl	1.9e-05	-0.56	19:50163132:G:A
Pituitary	eqtl	9.0e-04	-0.44	19:50163132:G:A
Brain Hypothalamus	eqtl	1.0e-02	-0.50	19:50163132:G:A
Lung	eqtl	3.6e-02	-0.37	19:50148423:G:A

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
182142	0.0629	33
182141	0.0280	5

Top tissues by expression

showing 100 of 208 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	93.99	gold quality
right testis	UBERON:0004534	93.89	gold quality
sperm	CL:0000019	93.14	gold quality
testis	UBERON:0000473	90.51	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.37	gold quality
adult organism	UBERON:0007023	71.85	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	71.25	gold quality
upper arm skin	UBERON:0004263	64.25	gold quality
buccal mucosa cell	CL:0002336	63.83	gold quality
secondary oocyte	CL:0000655	59.46	gold quality
tibialis anterior	UBERON:0001385	58.96	silver quality
nasal cavity epithelium	UBERON:0005384	57.45	gold quality
mucosa of paranasal sinus	UBERON:0005030	57.34	gold quality
parotid gland	UBERON:0001831	56.48	gold quality
vena cava	UBERON:0004087	55.42	gold quality
cardiac muscle of right atrium	UBERON:0003379	54.84	gold quality
superficial temporal artery	UBERON:0001614	54.80	gold quality
cortical plate	UBERON:0005343	54.75	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
pericardium	UBERON:0002407	53.72	gold quality
epithelial cell of pancreas	CL:0000083	53.62	gold quality
deltoid	UBERON:0001476	52.42	gold quality
pancreatic ductal cell	CL:0002079	51.51	silver quality
tendon of biceps brachii	UBERON:0008188	51.08	gold quality
lower lobe of lung	UBERON:0008949	50.52	silver quality
myocardium	UBERON:0002349	50.46	gold quality
oocyte	CL:0000023	47.84	gold quality
quadriceps femoris	UBERON:0001377	47.81	gold quality
trachea	UBERON:0003126	47.41	gold quality
nipple	UBERON:0002030	46.69	gold quality
ileal mucosa	UBERON:0000331	46.19	silver quality
lateral globus pallidus	UBERON:0002476	45.96	gold quality
vastus lateralis	UBERON:0001379	45.40	gold quality
sural nerve	UBERON:0015488	45.33	silver quality
amniotic fluid	UBERON:0000173	44.03	gold quality
primary visual cortex	UBERON:0002436	43.96	gold quality
epithelium of nasopharynx	UBERON:0001951	43.67	gold quality
layer of synovial tissue	UBERON:0007616	43.55	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
nucleus accumbens	UBERON:0001882	43.21	gold quality
right lobe of thyroid gland	UBERON:0001119	43.04	gold quality
Brodmann (1909) area 23	UBERON:0013554	43.02	gold quality
occipital lobe	UBERON:0002021	42.90	gold quality
substantia nigra	UBERON:0002038	42.75	gold quality
cartilage tissue	UBERON:0002418	42.70	gold quality
body of tongue	UBERON:0011876	42.54	gold quality
rectum	UBERON:0001052	42.44	gold quality
midbrain	UBERON:0001891	42.38	gold quality
right lung	UBERON:0002167	42.37	silver quality
caudate nucleus	UBERON:0001873	42.28	gold quality
skeletal muscle tissue	UBERON:0001134	42.11	gold quality
oviduct epithelium	UBERON:0004804	41.50	gold quality
islet of Langerhans	UBERON:0000006	41.46	gold quality
prostate gland	UBERON:0002367	41.28	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
medulla oblongata	UBERON:0001896	40.81	gold quality
epithelium of mammary gland	UBERON:0003244	40.79	gold quality
tongue	UBERON:0001723	40.70	gold quality
mammary duct	UBERON:0001765	40.64	gold quality
thyroid gland	UBERON:0002046	40.62	gold quality
jejunal mucosa	UBERON:0000399	40.59	gold quality
biceps brachii	UBERON:0001507	40.57	gold quality
gingival epithelium	UBERON:0001949	40.43	gold quality
putamen	UBERON:0001874	40.36	gold quality
germinal epithelium of ovary	UBERON:0001304	40.33	gold quality
esophagus squamous epithelium	UBERON:0006920	40.29	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	40.27	gold quality
jejunum	UBERON:0002115	40.18	gold quality
dorsal plus ventral thalamus	UBERON:0001897	40.15	gold quality
entorhinal cortex	UBERON:0002728	40.14	gold quality
globus pallidus	UBERON:0001875	40.12	gold quality
mucosa of sigmoid colon	UBERON:0004993	39.95	gold quality
bronchial epithelial cell	CL:0002328	39.88	gold quality
ectocervix	UBERON:0012249	39.88	silver quality
colonic mucosa	UBERON:0000317	39.87	gold quality
parietal lobe	UBERON:0001872	39.87	gold quality
bronchus	UBERON:0002185	39.85	gold quality
saphenous vein	UBERON:0007318	39.83	gold quality
urethra	UBERON:0000057	39.80	gold quality
heart right ventricle	UBERON:0002080	39.79	gold quality
endothelial cell	CL:0000115	39.75	gold quality
synovial joint	UBERON:0002217	39.70	gold quality
trabecular bone tissue	UBERON:0002483	39.70	gold quality
dorsal root ganglion	UBERON:0000044	39.68	gold quality
decidua	UBERON:0002450	39.65	gold quality
penis	UBERON:0000989	39.64	gold quality
gingiva	UBERON:0001828	39.64	gold quality
trigeminal ganglion	UBERON:0001675	39.63	gold quality
ganglionic eminence	UBERON:0004023	39.60	silver quality
inferior vagus X ganglion	UBERON:0005363	39.57	gold quality
superior surface of tongue	UBERON:0007371	39.56	gold quality
pylorus	UBERON:0001166	39.55	gold quality
renal medulla	UBERON:0000362	39.53	gold quality
pons	UBERON:0000988	39.51	gold quality
thymus	UBERON:0002370	39.50	gold quality
superior vestibular nucleus	UBERON:0007227	39.47	gold quality
cardia of stomach	UBERON:0001162	39.46	gold quality
parietal pleura	UBERON:0002400	39.45	gold quality
cerebellar vermis	UBERON:0004720	39.37	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.39
E-MTAB-7303	no	7.25

HPA expression

RNA tissue specificity: Tissue enriched

37 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Testis	tissue	25.0
Cerebellum	tissue	6.1
Olfactory bulb	tissue	3.0
Cerebral cortex	tissue	2.5
Retrosplenial and cingulate cortex	tissue	2.5
Basal ganglia	tissue	2.4
Hippocampal formation	tissue	2.4
Amygdala	tissue	2.3
Temporal cortex	tissue	2.3
Insular cortex	tissue	2.3
Entorhinal cortex	tissue	2.2
Prefrontal cortex	tissue	2.1
Hypothalamus	tissue	2.1
Septum	tissue	2.1
Motor cortex	tissue	2.0
Somatosensory cortex	tissue	1.9
Retrosplenial cortex	tissue	1.9
Substantia nigra	tissue	1.7
Occipital cortex	tissue	1.7
Thalamus	tissue	1.6
Ventral forebrain	tissue	1.6
Periaqueductal gray	tissue	1.6
Pons	tissue	1.5
Putamen	tissue	1.5
Midbrain	tissue	1.3
Medulla oblongata	tissue	1.1
Superior colliculi	tissue	1.1
Spinal cord	tissue	1.0
Postcentral gyrus	tissue	0.9
Nucleus accumbens	tissue	0.7
Corpus callosum	tissue	0.7
Hippocampus	tissue	0.6
Locus coeruleus	tissue	0.4
Choroid plexus	tissue	0.3
Skin 1	tissue	0.1
Thyroid gland	tissue	0.1
Prostate	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 188; highest nTPM — Subiculum (2.4), Dorsal hippocampus (1.9), Ventral hippocampus (1.7), Posterior cingulate cortex (1.1), Dorsal spinal cord (1.0).

Regulation

Is transcription factor: no

Functional genomics

gnomAD constraint: pLI 1.95e-05, LOEUF 1.25, missense Z 0.0361 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000293405 — one region, missense o/e 1.01.

Literature-anchored findings (GeneRIF, showing 1)

• Expression of IZUMO2 in colorectal cancer in association with clinicopathological features. (PMID:38484656)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Izumo2	ENSMUSG00000066500
rattus_norvegicus	Izumo2	ENSRNOG00000065701

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1922760) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 2 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased heart rate	1
increased cardiac muscle contractility	1

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
SNAR-A11	snRNA	100169954
SNAR-B1	snRNA	100170224
SNAR-D	snRNA	100170227
SNAR-B2	snRNA	100170217
MYH14	protein-coding	79784
KCNC3	protein-coding	3748
POLD1	protein-coding	5424
NR1H2	protein-coding	7376
NAPSA	protein-coding	9476

Protein

Protein identifiers

Izumo sperm-egg fusion protein 2 — Q6UXV1 (reviewed: Q6UXV1)

All UniProt accessions (4): M0QXA9, M0QZG1, M0R2L8, Q6UXV1

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Membrane.

Miscellaneous. Izumo is the name of a Japanese shrine to marriage.

Similarity. Belongs to the Izumo family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6UXV1-1	1	yes
Q6UXV1-2	2

RefSeq proteins (2): NP_001308378, NP_689571* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029389	IZUMO	Domain
IPR042920	IZUMO2	Family

Pfam: PF15005

UniProt features (8 total): topological domain 2, signal peptide 1, chain 1, transmembrane region 1, glycosylation site 1, splice variant 1, sequence variant 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UXV1-F1	86.82	0.68

Human Protein Atlas

Protein class: Transporters, Accessory Factors Involved in Transport, Predicted membrane proteins, UniProt - Evidence at transcript level

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): acrosome; mid piece

Antibody reliability (HPA): IH uncertain · IF approved

Functional residue map

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

Glycosylation sites (1)

Type	Positions
N-linked (glcnac…) asparagine	91

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-1300645	Acrosome Reaction and Sperm:Oocyte Membrane Binding	curated
R-HSA-1187000	Fertilization	—
R-HSA-1474165	Reproduction	—

MSigDB gene sets: 11 (showing top): REACTOME_FERTILIZATION, REACTOME_ACROSOME_REACTION_AND_SPERM_OOCYTE_MEMBRANE_BINDING, REACTOME_REPRODUCTION, ZIM3_TARGET_GENES, ZNF596_TARGET_GENES, GSE14769_UNSTIM_VS_240MIN_LPS_BMDM_DN, GSE2706_LPS_VS_R848_AND_LPS_2H_STIM_DC_DN, chr19q13, GSE2585_CTEC_VS_THYMIC_DC_UP, GSE5589_WT_VS_IL10_KO_LPS_AND_IL6_STIM_MACROPHAGE_45MIN_UP, GSE41176_UNSTIM_VS_ANTI_IGM_STIM_TAK1_KO_BCELL_1H_DN

GO Cellular Component (1): membrane (GO:0016020)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Fertilization	1
Reproduction	1

GO top-level categories

1 GO namespaces:

Category	Terms
cellular anatomical structure	1

Protein interactions and networks

STRING

showing 15 of 338 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IZUMO2	IZUMO3	Q5VZ72	812
IZUMO2	IZUMO4	Q1ZYL8	785
IZUMO2	IZUMO1	Q8IYV9	772
IZUMO2	SPATA25	Q9BR10	624
IZUMO2	TMEM95	Q3KNT9	586
IZUMO2	SPACA6	W5XKT8	577
IZUMO2	ISOC2	Q96AB3	521
IZUMO2	ADAM32	Q8TC27	510
IZUMO2	SPACA4	Q8TDM5	490
IZUMO2	MEIOC	A2RUB1	485
IZUMO2	PRM3	Q9NNZ6	460
IZUMO2	RASIP1	Q5U651	447
IZUMO2	ADAM2	P78326	438
IZUMO2	CATSPER4	Q7RTX7	434
IZUMO2	OR4K14	Q8NGD5	430

IntAct

BioGRID (2 interactions; top human partners by supporting records): LMNA (Two-hybrid), PARP4 (Proximity Label-MS)

Disease & clinical

Genetic variants

Variant evidence for IZUMO2: 41 ClinVar records (0 pathogenic / likely pathogenic).

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	4
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 30 predictions of 529):

Position(s)	Effect	Δscore	Sites
19:50158266–50158267	donor_loss	1.0000	5
19:50158349–50158350	acceptor_loss	1.0000	6
19:50159521	donor_gain	1.0000
19:50162961–50162962	donor_loss	1.0000	4
19:50162969	donor_gain	1.0000
19:50162984	donor_gain	1.0000
19:50158266	donor_loss	0.9900
19:50159529	donor_gain	0.9900
19:50162737–50162738	donor_loss	0.9900	4
19:50162814–50162815	acceptor_loss	0.9900	6

AlphaMissense

298 missense substitutions predicted likely pathogenic (of 1,418 scored), across 96 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F65	8	0.871	0.966
F44	8	0.832	0.956
C164	7	0.947	0.967
C133	7	0.934	0.964
C148	7	0.927	0.966
C138	7	0.916	0.953
F73	7	0.904	0.979
C24	7	0.903	0.945
C21	7	0.895	0.952
C158	7	0.889	0.950
C151	7	0.879	0.938
F64	7	0.841	0.958
F165	7	0.806	0.930
D147	7	0.750	0.834
D167	7	0.721	0.787
N215	7	0.714	0.785
M60	6	0.888	0.920
G75	6	0.875	0.944
R114	6	0.873	0.960
D103	6	0.693	0.866

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Rectum Adenocarcinoma)

Disease associations

OMIM: gene MIM:618895 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation	1
sodium arsenite	increases expression	1
perfluorooctanoic acid	increases expression	1
aflatoxin B2	increases methylation	1
perfluorooctane sulfonic acid	increases expression	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.