CGREF1

Summary

CGREF1 (cell growth regulator with EF-hand domain 1, HGNC:16962) is a protein-coding gene on chromosome 2p23.3, encoding Cell growth regulator with EF hand domain protein 1 (Q99674). Mediates cell-cell adhesion in a calcium-dependent manner.

Predicted to enable calcium ion binding activity. Predicted to be involved in negative regulation of cell population proliferation. Predicted to be located in extracellular region.

Source: NCBI Gene 10669 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 98 total
• MANE Select transcript: NM_006569

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16962
Approved symbol	CGREF1
Name	cell growth regulator with EF-hand domain 1
Location	2p23.3
Locus type	gene with protein product
Status	Approved
Aliases	CGR11
Ensembl gene	ENSG00000138028
Ensembl biotype	protein_coding
OMIM	606137
Entrez	10669

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000312734, ENST00000402394, ENST00000402550, ENST00000404694, ENST00000405600, ENST00000440612, ENST00000467539, ENST00000640154

RefSeq mRNA: 4 — MANE Select: NM_006569 NM_001166239, NM_001166240, NM_001301324, NM_006569

CCDS: CCDS33162, CCDS54339

Canonical transcript exons

ENST00000402394 — 6 exons

Exon	Start	End
ENSE00001522484	27118846	27119128
ENSE00001558231	27100594	27101888
ENSE00002299799	27104287	27104377
ENSE00003462078	27102526	27102591
ENSE00003464655	27102360	27102430
ENSE00003552979	27102097	27102221

Expression profiles

Bgee: expression breadth ubiquitous, 191 present calls, max score 92.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.0753 / max 70.3920, expressed in 1004 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
27446	3.0484	805
27445	1.0969	465
27444	0.3878	221
27443	0.3005	167
27441	0.1398	39
27442	0.1019	37

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	92.64	gold quality
nucleus accumbens	UBERON:0001882	92.29	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.25	gold quality
prefrontal cortex	UBERON:0000451	91.81	gold quality
cerebellar hemisphere	UBERON:0002245	91.47	gold quality
cerebellar cortex	UBERON:0002129	91.37	gold quality
cingulate cortex	UBERON:0003027	90.75	gold quality
anterior cingulate cortex	UBERON:0009835	90.63	gold quality
caudate nucleus	UBERON:0001873	90.13	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.06	gold quality
putamen	UBERON:0001874	89.58	gold quality
amygdala	UBERON:0001876	89.58	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.07	gold quality
cerebellum	UBERON:0002037	88.91	gold quality
neocortex	UBERON:0001950	87.56	gold quality
frontal cortex	UBERON:0001870	87.52	gold quality
left uterine tube	UBERON:0001303	86.99	gold quality
cortical plate	UBERON:0005343	86.91	gold quality
telencephalon	UBERON:0001893	86.33	gold quality
cerebral cortex	UBERON:0000956	85.80	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.38	gold quality
oocyte	CL:0000023	85.33	gold quality
forebrain	UBERON:0001890	84.54	gold quality
brain	UBERON:0000955	84.37	gold quality
central nervous system	UBERON:0001017	84.07	gold quality
right ovary	UBERON:0002118	84.06	gold quality
hypothalamus	UBERON:0001898	83.68	gold quality
Ammon’s horn	UBERON:0001954	83.58	gold quality
left ovary	UBERON:0002119	82.71	gold quality
temporal lobe	UBERON:0001871	82.62	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.74
E-GEOD-111727	no	56.06

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

29 targeting CGREF1, 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-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-148A-5P	99.30	68.27	1141
HSA-MIR-548V	99.29	69.47	1157
HSA-MIR-4727-5P	99.23	67.55	1154
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-3160-3P	99.07	64.78	955
HSA-MIR-4260	98.78	65.37	848
HSA-MIR-7113-3P	98.75	65.71	1120
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-6780A-3P	98.42	67.49	1518
HSA-MIR-4277	98.34	67.17	1323
HSA-MIR-4769-3P	97.95	68.17	1002
HSA-MIR-6817-5P	97.95	67.86	1026
HSA-MIR-4329	97.68	66.26	1003
HSA-MIR-3127-5P	97.52	65.24	786
HSA-MIR-558	97.50	67.16	977
HSA-MIR-1913	97.07	66.20	1417
HSA-MIR-3679-5P	94.75	66.46	862
HSA-MIR-1185-5P	94.47	65.95	725

Literature-anchored findings (GeneRIF, showing 1)

• Results clearly indicated that CGREF1 is a novel secretory protein, and plays an important role in regulation of AP-1 transcriptional activity and cell proliferation. (PMID:26022276)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cgref1	ENSMUSG00000029161
rattus_norvegicus	Cgref1	ENSRNOG00000007923
drosophila_melanogaster	CG17271	FBGN0038829
caenorhabditis_elegans		WBGENE00010075
caenorhabditis_elegans		WBGENE00011439
caenorhabditis_elegans		WBGENE00044634

Paralogs (1): MCFD2 (ENSG00000180398)

Protein

Protein identifiers

Cell growth regulator with EF hand domain protein 1 — Q99674 (reviewed: Q99674)

Alternative names: Cell growth regulatory gene 11 protein, Hydrophobestin

All UniProt accessions (4): A0A4W8W4R1, A0AA75LQY6, Q99674, F8WE80

UniProt curated annotations — full annotation on UniProt →

Function. Mediates cell-cell adhesion in a calcium-dependent manner. Able to inhibit growth in several cell lines.

Subcellular location. Secreted.

Post-translational modifications. Probably digested extracellularly by an unknown serine protease generating extremely hydrophobic bioactive peptides.

Domain organisation. Both EF-hands are required for function.

Induction. By p53/TP53.

Polymorphism. The number of repeats of 17 amino acids in the C-terminal is polymorphic and varies between 3 and 4. The majority of available transcripts lacks one of these repeats. The sequence shown, corresponding to the reference genome (GRCh38/hg38), contains 4 repeats.

Isoforms (3)

UniProt ID	Names	Canonical?
Q99674-4	4	yes
Q99674-2	2
Q99674-3	3

RefSeq proteins (4): NP_001159711, NP_001159712, NP_001288253, NP_006560* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR052110	MCFD2-like	Family

UniProt features (36 total): binding site 9, sequence variant 7, splice variant 5, compositionally biased region 4, repeat 4, domain 2, region of interest 2, signal peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99674-F1	62.75	0.25

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 (9): 82; 84; 86; 88; 93; 127; 129; 131; 138

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 80 (showing top): SATO_SILENCED_BY_DEACETYLATION_IN_PANCREATIC_CANCER, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, MYCMAX_01, GOBP_REGULATION_OF_CELL_CYCLE, HELLER_HDAC_TARGETS_SILENCED_BY_METHYLATION_UP, ZHAN_MULTIPLE_MYELOMA_LB_UP, HANSON_HRAS_SIGNALING_VIA_NFKB, MARTORIATI_MDM4_TARGETS_FETAL_LIVER_UP, AP2_Q6_01, MARSON_BOUND_BY_FOXP3_STIMULATED, JEPSEN_SMRT_TARGETS, BRUINS_UVC_RESPONSE_VIA_TP53_GROUP_B, FEVR_CTNNB1_TARGETS_UP, PURBEY_TARGETS_OF_CTBP1_AND_SATB1_UP, BONOME_OVARIAN_CANCER_SURVIVAL_SUBOPTIMAL_DEBULKING

GO Biological Process (3): cell adhesion (GO:0007155), negative regulation of cell population proliferation (GO:0008285), regulation of cell cycle (GO:0051726)

GO Molecular Function (3): calcium ion binding (GO:0005509), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (1): extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
cell cycle	1
regulation of cellular process	1
metal ion binding	1
binding	1
cation binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

548 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CGREF1	CGRRF1	Q99675	960
CGREF1	TP53	P04637	478
CGREF1	REEP1	Q9H902	435
CGREF1	BSCL2	Q96G97	430
CGREF1	PCNP	Q8WW12	412
CGREF1	EFCC1	Q9HA90	399
CGREF1	S100G	P29377	384
CGREF1	TMEM130	Q8N3G9	345
CGREF1	ARL16	Q0P5N6	337
CGREF1	EFCAB11	Q9BUY7	330
CGREF1	EFCAB7	A8K855	328
CGREF1	ENTHD1	Q8IYW4	326
CGREF1	EFHC2	Q5JST6	322
CGREF1	TCEANC	Q8N8B7	322
CGREF1	PCDHA1	Q9Y5I3	317

IntAct

12 interactions, top by confidence:

A	B	Type	Score
CGREF1	AQP6	psi-mi:“MI:0915”(physical association)	0.560
CGREF1	TNKS	psi-mi:“MI:0914”(association)	0.530
STUB1	DNAJC13	psi-mi:“MI:0914”(association)	0.530
CGREF1	CFTR	psi-mi:“MI:0915”(physical association)	0.370
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
CGREF1	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
CGREF1	HS3ST1	psi-mi:“MI:0914”(association)	0.350
SEC22A	CGREF1	psi-mi:“MI:0914”(association)	0.350
DNASE1L1	TIMP3	psi-mi:“MI:0914”(association)	0.350
CGREF1	AQP6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (30): CGREF1 (Two-hybrid), CGREF1 (Affinity Capture-MS), CGREF1 (Affinity Capture-RNA), PPP1R9B (Affinity Capture-MS), PLEKHG3 (Affinity Capture-MS), LMAN1 (Affinity Capture-MS), PTPRS (Affinity Capture-MS), TNKS (Affinity Capture-MS), TNKS2 (Affinity Capture-MS), CTSF (Affinity Capture-MS), VWA1 (Affinity Capture-MS), PEX5 (Affinity Capture-MS), ACTA2 (Affinity Capture-MS), GLB1L (Affinity Capture-MS), TOR1A (Affinity Capture-MS)

ESM2 similar proteins: A0A0J9YX94, A0A0J9YXQ4, A0A0J9YY54, A0A494C1R9, A5D7L8, A6NDY0, A6NKD2, A7E321, E9PGG2, F6SZT2, O14771, O19110, O75807, O88852, P0CV98, P0CV99, P0CW00, P0CW01, P0CW24, P17564, P78358, Q01534, Q0P5N2, Q15735, Q2KI51, Q2M329, Q587J8, Q5DTT8, Q5R5G8, Q5R6R8, Q5SV97, Q60465, Q62881, Q69ZB3, Q6P752, Q86V59, Q8BSI6, Q8IWY8, Q8N3D4, Q8VD63

Diamond homologs: P97586, Q5R8Z6, Q8K5B2, Q8K5B3, Q8NI22, Q8R1U2, Q99674

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	73
Likely benign	6
Benign	9

Top pathogenic / likely-pathogenic (0)

SpliceAI

1253 predictions. Top by Δscore:

Variant	Effect	Δscore
2:27099247:G:GT	donor_gain	1.0000
2:27099280:A:T	donor_gain	1.0000
2:27099283:GG:G	donor_gain	1.0000
2:27099284:GG:G	donor_gain	1.0000
2:27099414:TTGCA:T	acceptor_loss	1.0000
2:27099415:TGCA:T	acceptor_loss	1.0000
2:27099416:GCAGG:G	acceptor_loss	1.0000
2:27099417:CAGG:C	acceptor_loss	1.0000
2:27099418:A:AG	acceptor_gain	1.0000
2:27099418:AG:A	acceptor_gain	1.0000
2:27099418:AGGGC:A	acceptor_loss	1.0000
2:27099419:G:GG	acceptor_gain	1.0000
2:27099419:G:GT	acceptor_loss	1.0000
2:27099419:GG:G	acceptor_gain	1.0000
2:27099419:GGGCT:G	acceptor_gain	1.0000
2:27099439:T:TA	acceptor_gain	1.0000
2:27099440:G:A	acceptor_gain	1.0000
2:27099573:CCAGG:C	donor_gain	1.0000
2:27099574:CAGG:C	donor_gain	1.0000
2:27099575:AGG:A	donor_gain	1.0000
2:27099576:GG:G	donor_gain	1.0000
2:27099576:GGG:G	donor_gain	1.0000
2:27099577:GG:G	donor_gain	1.0000
2:27099577:GGT:G	donor_loss	1.0000
2:27099578:G:GG	donor_gain	1.0000
2:27102217:GAGAA:G	acceptor_gain	1.0000
2:27102218:AGAA:A	acceptor_gain	1.0000
2:27102219:GAA:G	acceptor_gain	1.0000
2:27102220:AA:A	acceptor_gain	1.0000
2:27102222:C:CC	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000066111 (2:27118569 G>A,T), RS1000075953 (2:27118806 G>T), RS1000189560 (2:27119311 G>A), RS1000198136 (2:27100311 T>C), RS1000593729 (2:27101010 C>A,T), RS1000710756 (2:27110933 A>C,G), RS1000791348 (2:27118067 T>C), RS1000804420 (2:27111073 C>A), RS1000952001 (2:27111630 G>A), RS1001037409 (2:27105735 C>T), RS1001105483 (2:27099031 A>G), RS1001235384 (2:27111349 C>G), RS1001256333 (2:27111660 G>A,C), RS1001341425 (2:27103964 C>T), RS1001352596 (2:27111787 A>C)

Disease associations

OMIM: gene MIM:606137 | disease phenotypes: MIM:615879, MIM:229800

GenCC curated gene-disease

Mondo (2): Tatton-Brown-Rahman overgrowth syndrome (MONDO:0014382), essential fructosuria (MONDO:0009252)

Orphanet (2): Tatton-Brown-Rahman syndrome (Orphanet:404443), Essential fructosuria (Orphanet:2056)

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST002345_18	Response to cytadine analogues (cytosine arabinoside)	9.000000e-06
GCST006810_21	Self-reported risk-taking behaviour	2.000000e-08
GCST010697_14	Cortical surface area (min-P)	2.000000e-09
GCST010698_75	Subcortical volume (min-P)	2.000000e-13
GCST010699_41	Brain morphology (min-P)	2.000000e-08
GCST010700_38	Cortical thickness (MOSTest)	3.000000e-08
GCST010701_56	Cortical surface area (MOSTest)	4.000000e-16
GCST010702_20	Subcortical volume (MOSTest)	2.000000e-64
GCST010703_76	Brain morphology (MOSTest)	1.000000e-16
GCST90010427_5	Left–right brain asymmetry	4.000000e-11

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008579	risk-taking behaviour
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538068	Fructosuria (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
Acetaminophen	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Tretinoin	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
deoxynivalenol	decreases expression	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	increases methylation	1
propiconazole	decreases expression	1
polyhexamethyleneguanidine	decreases expression	1
tebuconazole	decreases expression	1
2-palmitoylglycerol	increases expression	1
entinostat	increases expression	1
K 7174	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Bortezomib	increases expression	1
Sunitinib	decreases expression	1
Vorinostat	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dimethyl Sulfoxide	affects expression	1
Hydrogen Peroxide	affects expression	1
Lead	affects expression	1
Methapyrilene	increases methylation	1
Nicotine	increases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Urethane	affects expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation, increases methylation	1

Clinical trials (associated diseases)

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