FREM3

Summary

FREM3 (FRAS1 related extracellular matrix 3, HGNC:25172) is a protein-coding gene on chromosome 4q31.21, encoding FRAS1-related extracellular matrix protein 3 (P0C091). Extracellular matrix protein which may play a role in cell adhesion.

This gene encodes an integral membrane protein containing numerous CSPG (chondroitin sulfate proteoglycan element) repeats and Calx-beta domains. The protein belongs to the family of FRAS1/FREM extracellular matrix proteins and may play a role cell adhesion.

Source: NCBI Gene 166752 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 365 total — 2 pathogenic
• MANE Select transcript: NM_001168235

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25172
Approved symbol	FREM3
Name	FRAS1 related extracellular matrix 3
Location	4q31.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000183090
Ensembl biotype	protein_coding
OMIM	608946
Entrez	166752

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000329798, ENST00000508899

RefSeq mRNA: 1 — MANE Select: NM_001168235 NM_001168235

CCDS: CCDS54808

Canonical transcript exons

ENST00000329798 — 8 exons

Exon	Start	End
ENSE00001319566	143695491	143700675
ENSE00001481239	143577302	143577852
ENSE00001481240	143585844	143585993
ENSE00001481243	143621037	143621162
ENSE00001481245	143624108	143624338
ENSE00001481246	143627614	143627760
ENSE00001481247	143693113	143693202
ENSE00003669869	143611279	143611527

Expression profiles

Bgee: expression breadth ubiquitous, 107 present calls, max score 78.27.

Top tissues by expression

225 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	78.27	gold quality
middle temporal gyrus	UBERON:0002771	70.96	silver quality
Brodmann (1909) area 46	UBERON:0006483	69.40	gold quality
buccal mucosa cell	CL:0002336	68.89	gold quality
prefrontal cortex	UBERON:0000451	64.82	gold quality
superior frontal gyrus	UBERON:0002661	62.52	gold quality
frontal cortex	UBERON:0001870	61.74	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	60.57	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	60.41	gold quality
bone marrow cell	CL:0002092	58.96	gold quality
neocortex	UBERON:0001950	58.75	gold quality
nasal cavity mucosa	UBERON:0001826	58.49	gold quality
Brodmann (1909) area 9	UBERON:0013540	57.44	gold quality
Brodmann (1909) area 23	UBERON:0013554	57.31	silver quality
right frontal lobe	UBERON:0002810	56.78	gold quality
colonic epithelium	UBERON:0000397	56.29	silver quality
cerebral cortex	UBERON:0000956	54.81	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
anterior cingulate cortex	UBERON:0009835	53.89	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality
epithelial cell of pancreas	CL:0000083	52.93	gold quality
sural nerve	UBERON:0015488	52.55	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	52.17	gold quality
cerebellar vermis	UBERON:0004720	50.50	gold quality
myocardium	UBERON:0002349	50.25	gold quality
corpus callosum	UBERON:0002336	49.72	gold quality
calcaneal tendon	UBERON:0003701	49.72	gold quality
parietal lobe	UBERON:0001872	49.15	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.73
E-MTAB-6142	no	0.84

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

23 targeting FREM3, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-410-3P	99.27	69.98	2457
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-21-3P	99.21	68.95	1312
HSA-MIR-5581-3P	98.55	70.31	1161
HSA-MIR-302F	98.44	69.02	1776
HSA-MIR-4733-3P	98.35	65.20	994
HSA-MIR-1226-3P	97.51	66.32	1063
HSA-MIR-219B-3P	97.31	66.96	672
HSA-MIR-10400-3P	97.29	64.66	597
HSA-MIR-4674	97.29	64.62	597
HSA-MIR-3156-5P	96.93	67.36	800
HSA-MIR-4296	96.35	63.55	1233
HSA-MIR-4265	96.18	64.68	557
HSA-MIR-4322	96.18	64.85	539

Literature-anchored findings (GeneRIF, showing 1)

• The combined effect of the EHD3 and FREM3 genes may play an important role in developing major depressive disorder. (PMID:22337703)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	frem3	ENSDARG00000074677
mus_musculus	Frem3	ENSMUSG00000042353
rattus_norvegicus	Frem3	ENSRNOG00000039152

Paralogs (7): SLC8A3 (ENSG00000100678), SLC8A2 (ENSG00000118160), FRAS1 (ENSG00000138759), FREM2 (ENSG00000150893), ADGRV1 (ENSG00000164199), FREM1 (ENSG00000164946), SLC8A1 (ENSG00000183023)

Protein

Protein identifiers

FRAS1-related extracellular matrix protein 3 — P0C091 (reviewed: P0C091)

All UniProt accessions (1): P0C091

UniProt curated annotations — full annotation on UniProt →

Function. Extracellular matrix protein which may play a role in cell adhesion.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Domain organisation. The Calx-beta domains bind calcium with high affinity and undergo a major conformational shift upon binding.

Similarity. Belongs to the FRAS1 family.

RefSeq proteins (1): NP_001161707* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003644	Calx_beta	Domain
IPR038081	CalX-like_sf	Homologous_superfamily
IPR039005	CSPG_rpt	Repeat
IPR045658	FRAS1-rel_N	Domain
IPR051561	FRAS1_ECM	Family

Pfam: PF03160, PF16184, PF19309

UniProt features (23 total): repeat 12, glycosylation site 4, domain 3, sequence variant 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0C091-F1	76.32	0.04

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 (4): 846, 1368, 1374, 1588

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 22 (showing top): GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, GOCC_BASEMENT_MEMBRANE, GOBP_EPITHELIAL_STRUCTURE_MAINTENANCE, GOBP_CELL_SUBSTRATE_ADHESION, GOBP_CELL_MATRIX_ADHESION, GOBP_HOMEOSTATIC_PROCESS, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY, GOCC_EXTERNAL_ENCAPSULATING_STRUCTURE, MIR4639_5P, MIR4437, MIR3156_5P, chr4q31, DESCARTES_FETAL_LUNG_BRONCHIOLAR_AND_ALVEOLAR_EPITHELIAL_CELLS, GSE17974_CTRL_VS_ACT_IL4_AND_ANTI_IL12_0.5H_CD4_TCELL_UP, GSE17974_CTRL_VS_ACT_IL4_AND_ANTI_IL12_1H_CD4_TCELL_UP

GO Biological Process (3): cell communication (GO:0007154), cell adhesion (GO:0007155), anatomical structure morphogenesis (GO:0009653)

GO Molecular Function (1): metal ion binding (GO:0046872)

GO Cellular Component (5): basement membrane (GO:0005604), obsolete extracellular space (GO:0005615), membrane (GO:0016020), extracellular region (GO:0005576), extracellular matrix (GO:0031012)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
cellular anatomical structure	2
developmental process	1
anatomical structure development	1
cation binding	1
extracellular matrix	1
external encapsulating structure	1

Protein interactions and networks

STRING

1218 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FREM3	GYPE	P15421	729
FREM3	GYPB	P06028	696
FREM3	GYPA	P02724	693
FREM3	ARL14	Q8N4G2	590
FREM3	GRIP1	Q9Y3R0	564
FREM3	USP38	Q8NB14	542
FREM3	HBB	P02023	540
FREM3	SMARCA5	O60264	525
FREM3	ATP2B4	P23634	496
FREM3	MTRR	Q9UBK8	482
FREM3	ANAPC10	Q9UM13	476
FREM3	RPS6KL1	Q9Y6S9	475
FREM3	INPP4B	O15327	474
FREM3	LAMP5	Q9UJQ1	467
FREM3	IGFBP7	Q16270	462
FREM3	ST3GAL1	Q11201	462

IntAct

3 interactions, top by confidence:

A	B	Type	Score
P		psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350

BioGRID (4): FREM3 (Affinity Capture-MS), FREM3 (Affinity Capture-MS), FREM3 (Proximity Label-MS), RAB20 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A140LHF2, A6H8M9, D3YX43, O08644, O15197, O55134, O70394, O70540, O75309, O88338, P0C091, P0C0K6, P0C0K7, P0DP72, P21709, P40223, P59862, P70289, Q00657, Q04912, Q0V8J4, Q28634, Q501P1, Q53RD9, Q58Y75, Q5DRE2, Q5H8B9, Q5R6F5, Q5SZK8, Q60750, Q63315, Q64612, Q6MG64, Q6NVD0, Q6PFX6, Q6UVK1, Q76MJ5, Q7TN88, Q7Z442, Q86UP0

Diamond homologs: P0C091, Q5H8B9, Q5H8C1, Q5SZK8, Q684R7, Q6NVD0, Q86XX4, Q9GV77, Q9VDG5, Q95J96, Q95LC6, Q9R0Q8, Q80T14, A7X406, A7X409, P20693, P25031, P28163, Q07108, Q25116, Q26646, Q6X5S5, I7MD46, P02457, P28481, P41413, Q04592, Q2KIT5, Q3U962, Q4G063, Q4V7M2, Q63415, Q6UXH1, Q6ZWJ8, Q9CYA0, Q9NJ15, Q9NZV1, Q9UPR5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	331
Likely benign	27
Benign	3

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
59481	GRCh38/hg38 4q31.21(chr4:140605955-144317039)x1	Pathogenic
814610	GRCh37/hg19 4q31.1-31.21(chr4:139531815-146095109)x1	Pathogenic

SpliceAI

1297 predictions. Top by Δscore:

Variant	Effect	Δscore
4:143577853:C:CC	acceptor_gain	1.0000
4:143611525:AACC:A	acceptor_loss	1.0000
4:143621163:C:CC	acceptor_gain	1.0000
4:143624103:CATA:C	donor_loss	1.0000
4:143624104:ATAC:A	donor_loss	1.0000
4:143624105:TA:T	donor_loss	1.0000
4:143624106:A:AC	donor_gain	1.0000
4:143624106:A:T	donor_loss	1.0000
4:143624107:C:CC	donor_gain	1.0000
4:143624107:CCAT:C	donor_gain	1.0000
4:143624334:AATGC:A	acceptor_gain	1.0000
4:143624336:TGC:T	acceptor_gain	1.0000
4:143624337:GCC:G	acceptor_loss	1.0000
4:143624338:CCTG:C	acceptor_loss	1.0000
4:143624339:C:CA	acceptor_loss	1.0000
4:143624339:C:CC	acceptor_gain	1.0000
4:143627612:A:AC	donor_gain	1.0000
4:143627613:C:CT	donor_gain	1.0000
4:143693106:GACTT:G	donor_loss	1.0000
4:143693107:ACTT:A	donor_loss	1.0000
4:143693108:CTTA:C	donor_loss	1.0000
4:143693109:TTACC:T	donor_loss	1.0000
4:143693110:TACCA:T	donor_loss	1.0000
4:143693111:A:AC	donor_gain	1.0000
4:143693111:A:C	donor_loss	1.0000
4:143693112:C:CA	donor_loss	1.0000
4:143693112:C:CC	donor_gain	1.0000
4:143693112:CCA:C	donor_gain	1.0000
4:143693198:GTCAG:G	acceptor_gain	1.0000
4:143693199:TCAG:T	acceptor_gain	1.0000

AlphaMissense

14114 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:143700319:G:C	F119L	0.965
4:143700319:G:T	F119L	0.965
4:143700321:A:G	F119L	0.965
4:143700332:A:C	F115C	0.954
4:143698654:G:C	F674L	0.952
4:143698654:G:T	F674L	0.952
4:143698656:A:G	F674L	0.952
4:143699922:A:C	Y252D	0.951
4:143700332:A:G	F115S	0.947
4:143699644:G:C	F344L	0.943
4:143699644:G:T	F344L	0.943
4:143699646:A:G	F344L	0.943
4:143698743:A:G	W645R	0.941
4:143698743:A:T	W645R	0.941
4:143699645:A:G	F344S	0.941
4:143700121:G:C	S185R	0.941
4:143700121:G:T	S185R	0.941
4:143700123:T:G	S185R	0.941
4:143699163:A:C	Y505D	0.940
4:143699545:G:C	F377L	0.939
4:143699545:G:T	F377L	0.939
4:143699547:A:G	F377L	0.939
4:143696911:G:C	F1255L	0.938
4:143696911:G:T	F1255L	0.938
4:143696913:A:G	F1255L	0.938
4:143698317:A:C	Y787D	0.933
4:143699921:T:G	Y252S	0.931
4:143700331:G:C	F115L	0.931
4:143700331:G:T	F115L	0.931
4:143700333:A:G	F115L	0.931

dbSNP variants (sampled 300 via entrez): RS1000023954 (4:143681647 A>G), RS1000065034 (4:143682366 A>C,G), RS1000074296 (4:143690531 A>G), RS1000090696 (4:143600373 T>C), RS1000118095 (4:143630818 A>C), RS1000128449 (4:143646460 A>C), RS1000164112 (4:143679003 G>A), RS1000172413 (4:143672080 C>A,T), RS1000207915 (4:143589047 G>C), RS1000223676 (4:143630255 A>G,T), RS1000228821 (4:143646742 G>A), RS1000243733 (4:143626410 A>G), RS1000288614 (4:143640031 T>A,C), RS1000304849 (4:143585287 C>G), RS1000318659 (4:143594584 T>G)

Disease associations

OMIM: gene MIM:608946 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST003145_1	Severe malaria	4.000000e-11
GCST003145_3	Severe malaria	1.000000e-10
GCST007954_44	Glycated hemoglobin levels	3.000000e-15
GCST010725_4	Malaria	4.000000e-10
GCST010725_84	Malaria	7.000000e-11
GCST010725_89	Malaria	7.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004541	HbA1c measurement

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
Benzo(a)pyrene	affects methylation, decreases methylation, increases mutagenesis	2
methylmercuric chloride	decreases expression	1
bisphenol S	decreases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Copper	affects cotreatment, decreases expression	1
Dronabinol	decreases expression	1

Clinical trials (associated diseases)

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