FREY1

Summary

FREY1 (Frey regulator of sperm-oocyte fusion 1, HGNC:37213) is a protein-coding gene on chromosome 11p11.2, encoding Protein Frey 1 (C9JXX5). Key regulator for male fertility expressed transiently in round spermatids where it recruits IZUMO1 at the endoplasmic reticulum (ER) membrane and coordinates the oolemmal binding multimeric complex (IZUMO1 complex) assembly.

Predicted to enable protein-macromolecule adaptor activity. Predicted to be involved in fusion of sperm to egg plasma membrane involved in single fertilization; maintenance of protein localization in endoplasmic reticulum; and sperm-egg recognition. Predicted to act upstream of or within several processes, including protein modification process; protein stabilization; and spermatid development. Predicted to be located in endoplasmic reticulum. Predicted to be active in endoplasmic reticulum membrane.

Source: NCBI Gene 143678 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 6 total
• MANE Select transcript: NM_001080446

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:37213
Approved symbol	FREY1
Name	Frey regulator of sperm-oocyte fusion 1
Location	11p11.2
Locus type	gene with protein product
Status	Approved
Aliases	Frey
Ensembl gene	ENSG00000234776
Ensembl biotype	protein_coding
Entrez	143678

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 retained_intron

ENST00000449465, ENST00000632252

RefSeq mRNA: 1 — MANE Select: NM_001080446 NM_001080446

CCDS: CCDS44577

Canonical transcript exons

ENST00000449465 — 3 exons

Exon	Start	End
ENSE00001700239	45906534	45906690
ENSE00001719844	45906869	45906942
ENSE00001740890	45907145	45907271

Expression profiles

Bgee: expression breadth ubiquitous, 149 present calls, max score 92.38.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0754 / max 75.7823, expressed in 3 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
119486	0.0299	3
119484	0.0251	3
119487	0.0154	3
119485	0.0050	3

Top tissues by expression

254 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	92.38	gold quality
left testis	UBERON:0004533	91.51	gold quality
right testis	UBERON:0004534	90.32	gold quality
sperm	CL:0000019	88.30	gold quality
testis	UBERON:0000473	87.32	gold quality
pancreatic ductal cell	CL:0002079	62.31	silver quality
mucosa of transverse colon	UBERON:0004991	59.55	gold quality
cerebellar hemisphere	UBERON:0002245	59.29	gold quality
cerebellar cortex	UBERON:0002129	59.16	gold quality
right hemisphere of cerebellum	UBERON:0014890	58.89	gold quality
cerebellum	UBERON:0002037	57.90	gold quality
lower esophagus mucosa	UBERON:0035834	57.90	gold quality
ganglionic eminence	UBERON:0004023	57.47	gold quality
bone marrow cell	CL:0002092	56.59	silver quality
cortical plate	UBERON:0005343	56.37	gold quality
epithelial cell of pancreas	CL:0000083	54.93	gold quality
ventricular zone	UBERON:0003053	54.35	gold quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality
metanephros cortex	UBERON:0010533	53.45	gold quality
right coronary artery	UBERON:0001625	52.94	gold quality
body of stomach	UBERON:0001161	52.93	gold quality
adult mammalian kidney	UBERON:0000082	52.74	gold quality
right lobe of liver	UBERON:0001114	52.51	gold quality
tibialis anterior	UBERON:0001385	52.01	silver quality
heart right ventricle	UBERON:0002080	51.46	gold quality
adenohypophysis	UBERON:0002196	51.43	gold quality
granulocyte	CL:0000094	51.28	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.65

Regulation

Is transcription factor: no

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Frey1	ENSMUSG00000044916
rattus_norvegicus	Frey1	ENSRNOG00000006884

Protein

Protein identifiers

Protein Frey 1 — C9JXX5 (reviewed: C9JXX5)

Alternative names: Frey regulator of sperm-oocyte fusion 1

All UniProt accessions (1): C9JXX5

UniProt curated annotations — full annotation on UniProt →

Function. Key regulator for male fertility expressed transiently in round spermatids where it recruits IZUMO1 at the endoplasmic reticulum (ER) membrane and coordinates the oolemmal binding multimeric complex (IZUMO1 complex) assembly. Upon complete assembly of the IZUMO1 complex, its ER retention is released, facilitating IZUMO1 complex export to the acrosome. Through the interaction with SPPL2C, inhibits its intramembrane protease activity directly accessing the catalytic center of an I-CLiP.

Subunit / interactions. Interacts with SPPL2C (via active sites); the interaction stabilizes FREY1 protein and inhibits SPPL2C proteolytic activity. Interacts with IZUMO1; the interaction retains IZUMO1 at the endoplasmic reticulum membrane and coordinates IZUMO1 complex assembly.

Subcellular location. Endoplasmic reticulum membrane.

RefSeq proteins (1): NP_001073915* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR031748	Frey	Family

Pfam: PF15878

UniProt features (4 total): chain 1, transmembrane region 1, region of interest 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-C9JXX5-F1	70.16	0.04

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 58 (showing top): GOBP_SINGLE_FERTILIZATION, GOBP_PROTEIN_N_LINKED_GLYCOSYLATION, GOBP_MEMBRANE_FUSION, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_MALE_GAMETE_GENERATION, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_PROTEIN_LOCALIZATION_TO_ENDOPLASMIC_RETICULUM, GOBP_MAINTENANCE_OF_LOCATION, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOBP_PROTEIN_STABILIZATION, GOBP_MAINTENANCE_OF_PROTEIN_LOCALIZATION_IN_ORGANELLE, GOBP_SPERM_EGG_RECOGNITION, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION

GO Biological Process (13): protein N-linked glycosylation (GO:0006487), intracellular calcium ion homeostasis (GO:0006874), spermatid development (GO:0007286), fusion of sperm to egg plasma membrane involved in single fertilization (GO:0007342), gene expression (GO:0010467), protein ubiquitination (GO:0016567), sperm-egg recognition (GO:0035036), maintenance of protein localization in endoplasmic reticulum (GO:0035437), protein stabilization (GO:0050821), protein localization involved in acrosome reaction (GO:0060476), protein-containing complex assembly (GO:0065003), spermatogenesis (GO:0007283), single fertilization (GO:0007338)

GO Molecular Function (1): protein-macromolecule adaptor activity (GO:0030674)

GO Cellular Component (3): endoplasmic reticulum membrane (GO:0005789), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
single fertilization	2
glycoprotein biosynthetic process	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
germ cell development	1
spermatid differentiation	1
cellular process involved in reproduction in multicellular organism	1
macromolecule biosynthetic process	1
protein modification by small protein conjugation	1
cell-cell recognition	1
endoplasmic reticulum	1
protein localization to endoplasmic reticulum	1
maintenance of protein localization in organelle	1
regulation of protein stability	1
acrosome reaction	1
intracellular protein localization	1
actin filament-based process	1
cellular component assembly	1
protein-containing complex organization	1
developmental process involved in reproduction	1
male gamete generation	1
fertilization	1
protein binding	1
molecular adaptor activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

186 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FREY1	OR2A2	Q6IF42	735
FREY1	FAM194C	Q8ND61	567
FREY1	ZNF782	Q6ZMW2	543
FREY1	TEX38	Q6PEX7	542
FREY1	ZNF550	Q7Z398	541
FREY1	OR4S1	Q8NGB4	475
FREY1	ARRDC5	A6NEK1	475
FREY1	FIMP1	Q96LL3	419
FREY1	ZNF419	Q96HQ0	419
FREY1	MEIKIN	A0A087WXM9	419
FREY1	ODF4	Q2M2E3	418
FREY1	ADAD2	Q8NCV1	404
FREY1	MEIG1	Q5JSS6	403
FREY1	ACTL7B	Q9Y614	398
FREY1	ERVMER34-1	Q9H9K5	397

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A0A1B0GUA5, A0A286YF18, A0A3G1VU77, A0A3G1VU78, A0JNN8, A5PK62, C9JXX5, D2HJ50, P01172, P07480, P0C171, P0C172, P0DJK0, P0DJK1, P11242, P18509, P20800, P22389, P22466, P23943, P52511, P82271, Q08648, Q1RMJ9, Q5NRP8, Q5NRQ0, Q6VUC0, Q6VUP9, Q70KG2, Q765Z5, Q867A9, Q867D0, Q8CF31, Q8K1M5, Q8MJV4, Q8MJW9, Q8NG41, Q8SQD7, Q91W27, Q969E3

Diamond homologs: A5PK62, C9JXX5, D2HJ50, Q8CF31

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	3
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

177 predictions. Top by Δscore:

Variant	Effect	Δscore
11:45907142:CA:C	donor_loss	0.9300
11:45907143:ACCTC:A	donor_loss	0.9300
11:45907144:C:CA	donor_loss	0.9300
11:45907145:C:G	donor_loss	0.9000
11:45906691:C:CC	acceptor_gain	0.8900
11:45907146:T:TA	donor_gain	0.8900
11:45906687:TAGT:T	acceptor_gain	0.8800
11:45907098:TCC:T	donor_gain	0.8400
11:45907175:G:GA	donor_gain	0.8400
11:45906689:GTCT:G	acceptor_loss	0.8000
11:45906690:TCT:T	acceptor_loss	0.8000
11:45906691:CT:C	acceptor_loss	0.8000
11:45906689:GT:G	acceptor_gain	0.7900
11:45906686:ATAGT:A	acceptor_gain	0.7400
11:45906868:CCAT:C	donor_gain	0.7400
11:45906869:CATC:C	donor_gain	0.7400
11:45907092:A:AC	donor_gain	0.7300
11:45907252:CA:C	donor_gain	0.7000
11:45907253:A:C	donor_gain	0.6900
11:45906688:AGT:A	acceptor_gain	0.6600
11:45906872:C:CT	donor_gain	0.6600
11:45907098:T:TA	donor_gain	0.6600
11:45906871:TCC:T	donor_gain	0.6500
11:45907146:T:A	donor_loss	0.6100
11:45907251:A:AC	donor_gain	0.6000
11:45907252:C:CC	donor_gain	0.6000
11:45906873:C:CT	donor_gain	0.5800
11:45907249:C:T	donor_gain	0.5600
11:45906865:C:CT	donor_gain	0.5500
11:45906866:T:TC	donor_gain	0.5500

AlphaMissense

607 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:45906617:C:A	K83N	0.937
11:45906617:C:G	K83N	0.937
11:45906684:C:A	G61V	0.864
11:45906872:C:G	D58H	0.861
11:45906871:T:A	D58V	0.857
11:45906618:T:G	K83T	0.854
11:45906675:G:T	P64H	0.849
11:45906681:A:G	I62T	0.849
11:45906671:C:A	K65N	0.846
11:45906671:C:G	K65N	0.846
11:45906690:T:A	D59V	0.841
11:45906591:T:C	Y92C	0.827
11:45906592:A:G	Y92H	0.827
11:45906685:C:A	G61C	0.807
11:45906618:T:A	K83M	0.805
11:45906676:G:T	P64T	0.804
11:45906869:C:G	D59H	0.801
11:45906676:G:A	P64S	0.791
11:45906619:T:C	K83E	0.788
11:45906870:A:C	D58E	0.787
11:45906870:A:T	D58E	0.787
11:45906681:A:C	I62S	0.778
11:45906685:C:G	G61R	0.769
11:45906688:A:G	Y60H	0.740
11:45906872:C:A	D58Y	0.739
11:45906684:C:T	G61D	0.737
11:45906871:T:G	D58A	0.731
11:45906689:G:C	D59E	0.723
11:45906689:G:T	D59E	0.723
11:45906591:T:G	Y92S	0.722

dbSNP variants (sampled 300 via entrez): RS1000372980 (11:45907982 G>T), RS1000697853 (11:45909007 A>G), RS1001700743 (11:45909069 G>A), RS1001960913 (11:45908277 T>C), RS1002021223 (11:45908017 G>A), RS1004243039 (11:45906230 G>A), RS1004363938 (11:45906428 C>A,G,T), RS1004457702 (11:45907928 C>G,T), RS1004790298 (11:45907101 A>C), RS1004838208 (11:45907555 C>T), RS1005107768 (11:45907387 G>A), RS1005461449 (11:45908983 C>A,T), RS1005823030 (11:45907768 G>C), RS1007561356 (11:45908641 T>C), RS1007616764 (11:45908810 C>A,G)

Disease associations

OMIM: gene `` | disease phenotypes: MIM:266265

GenCC curated gene-disease

Mondo (1): leukocyte adhesion deficiency type II (MONDO:0009953)

Orphanet (2): Leukocyte adhesion deficiency (Orphanet:2968), Leukocyte adhesion deficiency type II (Orphanet:99843)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007825_1	Alzheimer’s disease or fasting glucose levels (pleiotropy)	2.000000e-13

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535755	Congenital disorder of glycosylation, type 2C (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	1
abrine	increases expression	1
licochalcone B	increases expression	1
Sunitinib	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	decreases expression	1
Rotenone	decreases expression	1
Valproic Acid	increases methylation	1
Lactic Acid	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03354533	PHASE1/PHASE2	COMPLETED	Study of ORL-1F (L-fucose) in Patients With Leukocyte Adhesion Deficiency Type II