FREM1
protein-codingFRAS1 related extracellular matrix 1, the group of C-type lectin domain containing
Gene summary
The products of this gene play important roles both in embryonic development and as a modulator of the innate immune responses and inflammation. This gene encodes an extracellular matrix protein that is restricted to the dermis. It is secreted and forms complexes with FREM2 and FRAS1 gene products and is required to maintain epidermal adhesion during embryonic development. Pathogenic mutations in this gene have been implicated in Manitoba oculotrichoanal (MOTA) syndrome, bifid nose with or without anorectal and renal anomalies (BNAR syndrome), and congenital diaphragmatic hernia (CDH). A 715 aa isoform of this gene known as TILRR (Toll-like interleukin-receptor regulator) is expressed from an alternate promoter and is involved in controlling the inflammatory process. The encoded protein is a cell surface proteoglycan that is a co-receptor for IL-1 receptor type I (IL1RI). TILRR increases IL1R1 expression levels and regulates receptor function, leading to amplified activation of NF-kappaB and inflammatory responses. [provided by RefSeq, Apr 2026]
- C9orf154
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~173.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009560
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0013774
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009560
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009560
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012165
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013774
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013774
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009560
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0012165
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012165
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013774
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009560
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009560
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0019636
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0018065
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Dermatologic; Gastrointestinal; Musculoskeletal; Ophthalmologic; Renal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FREM1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001379081.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 31 | 241 | 13 | 286 | |
| missense | 1 | 2 | 794 | 69 | 7 | 873 |
| nonsense | 6 | 16 | 2 | 24 | ||
| start loss | 1 | 1 | ||||
| frameshift | 10 | 20 | 4 | 34 | ||
| splice donor/acceptor (+/-2bp) | 2 | 21 | 3 | 26 | ||
| Total | 20 | 60 | 834 | 310 | 20 | 1244 |
Highest pathogenic variant AF is 0.00021799868
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001366010.1 | 36 | MANE Select | |
| Ensembl | ENSP00000370262.3 | 36 | MANE Select | |
| RefSeq | NP_001171175.1 | 13 | Standard | |
| RefSeq | NP_001356987.1 | 11 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| frem1a | Danio rerio | Structure: dorsal fin Quality: has fewer parts of type abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- cell communication
- cell-matrix adhesion
- craniofacial suture morphogenesis
Molecular Function
- carbohydrate binding
- metal ion binding
Cellular Component
- basement membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000422223
- Coding exons
- 36
- Length
- 176330
- Individuals with no LoFs
- 124467
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 211
- Defined
- 124679
- p
- 0.000851
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -3.51 | 1485 | 1.15e+3 | 1.29 | 0.0000597 | 14317 |
| Missense (PolyPhen) | 346 | 286.77 | 1.2065 | 3704 | ||
| Synonymous | -5.00 | 575 | 441 | 1.30 | 0.0000246 | 4182 |
| Loss of Function | 0.608 | 83 | 89.2 | 0.931 | 0.00000428 | 1126 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0015 | 0.0014 | notable |
| Latino/Admixed American | 0.00092 | 0.00090 | rare |
| Ashkenazi Jewish | 0.00030 | 0.00030 | rare |
| East Asian | 0.00057 | 0.00056 | rare |
| Finnish | 0.00070 | 0.00070 | rare |
| European (Non-Finnish) | 0.00072 | 0.00070 | rare |
| South Asian | 0.0017 | 0.0016 | notable |
| Other | 0.00050 | 0.00050 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Extracellular matrix protein that plays a role in epidermal differentiation and is required for epidermal adhesion during embryonic development. {ECO:0000250}.;
- Disease
- DISEASE: Bifid nose, with or without anorectal and renal anomalies (BNAR) [MIM:608980]: A disease characterized by the presence of a bifid nose usually associated with renal agenesis and anorectal malformations. A bifid nose is a congenital deformity due to failure of the paired nasal processes to fuse to a single midline organ during early gestation. {ECO:0000269|PubMed:19732862}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Manitoba oculotrichoanal syndrome (MOTA) [MIM:248450]: A rare condition defined by eyelid colobomas, cryptophthalmos, and anophthalmia/microphthalmia, an aberrant hairline, a bifid or broad nasal tip, and gastrointestinal anomalies such as omphalocele and anal stenosis. {ECO:0000269|PubMed:21507892, ECO:0000269|PubMed:28111185}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Trigonocephaly 2 (TRIGNO2) [MIM:614485]: A keel-shaped deformation of the forehead, caused by premature fusion of the metopic sutures. It results in a triangular shape of the head. {ECO:0000269|PubMed:21931569}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.102
Intolerance Scores
- LoFtool
- 0.995
- RVIS EVS
- -0.63
- RVIS percentile EVS
- 17.04
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.548
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | Medium | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |