FGF12
protein-codingfibroblast growth factor 12, the group of Fibroblast growth factor family
Gene summary
The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth, and invasion. This growth factor lacks the N-terminal signal sequence present in most of the FGF family members, but it contains clusters of basic residues that have been demonstrated to act as a nuclear localization signal. When transfected into mammalian cells, this protein accumulated in the nucleus, but was not secreted. The specific function of this gene has not yet been determined. [provided by RefSeq, Dec 2019]
- FGF12B
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~628.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0015263
Submitter: ClinGen
FGF12 encodes the fibroblast growth factor 12, a sodium channel binding protein that binds to Nav1.5 (PMID: 12401812). Hennessey et al. first suggested a relationship between FGF12 and autosomal dominant Brugada syndrome in 2013 (PMID: 24096171). Following screening of a cohort of 102 patients with Brugada syndrome, the authors identified one rare missense variant in the gene (c.20A>G, p.Gln7Arg). The recombinant p.Gln7Arg protein was shown to have a decreased binding affinity for Nav1.5 and resulted in decreased sodium current density in a transfected FGF13 KO rat cardiomyocyte model. This variant is also absent from gnomAD v4.1. However, since this initial publication, there has been no further compelling genetic evidence corroborating this gene-disease relationship. Indeed, two separate studies have specifically considered the prevalence of FGF12 variants in Brugada syndrome cohorts and have not found any rare variants within the coding exons of the gene (PMID: 25650408, 26220970). Additionally, no cardiac features have been reported in FGF12 homozygous knockout models (PMIDs: 30065296, 17678857). Li et al. have also reported several FGF12 variants in a cohort of patients with idiopathic ventricular tachycardia however more evidence is required to substantiate this relationship (PMID: 28775062). This gene-disease relationship was evaluated on December 9 2025, by the Hereditary Cardiovascular Disorders GCEP. Given the absence of compelling clinical genetic data, this gene-disease classification was disputed. This classification was approved by the ClinGen Hereditary Cardiovascular Disorders GCEP on December 9, 2025 (in accordance with SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0014949
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014949
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0018614
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0100062
Submitter: ClinGen
*FGF12* encodes a sodium channel-binding protein, member of the fibroblast growth factor homologous factor family, involved in the positive regulation of voltage-gated sodium channel activity. *FGF12* was first reported in relation to developmental and epileptic encephalopathy in 2016 (Siekierska et al., PMIDs: 27164707). The mechanism of disease is heterozygous missense variants with a gain-of-function effect on sodium channel activity (PMID: 27164707, 36029553). The clinical presentation typically includes infantile-onset generalized and/or focal seizures, developmental delay, intellectual disability, and cerebellar or cerebral atrophy. Autism spectrum disorder has been reported in several cases. Three missense variants in this gene have been reported in at least 21 probands in 10 publications (PMIDs: 27164707, 27830185, 27872899, 28506426, 29699863, 30951195, 31292943, 32645220, 33287870, 36029553), including a recurrent variant, p.Arg52His, observed in 14 unrelated individuals. Variants usually occur *de novo* or are inherited from parents with germline or somatic mosaicism. In addition, two studies reported three probands with overlapping phenotypes carrying gene duplications resulting in loss of function (PMIDs: 28144627, 32524056, 36029553); these variants were not scored in this curation due to their different molecular mechanism. This gene-disease relationship is also supported by experimental evidence, including biochemical function (PMID: 33245860), functional alteration in cultured cells (PMIDs: 27164707, 36029553) and animal models in zebrafish (PMID: 27164707) and mice (PMID: 33982289). In summary, there is definitive evidence supporting the relationship between *FGF12* and autosomal dominant developmental and epileptic encephalopathy. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 1, 2023 (SOP version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0014949
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014949
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Neurologic
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 FGF12 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004113.6. 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 | 27 | 1 | 29 | ||
| missense | 3 | 61 | 16 | 9 | 89 | |
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 3 | 4 | |||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 4 | 69 | 43 | 10 | 126 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004104.3 | 5 | MANE Select | |
| Ensembl | ENSP00000393686.1 | 5 | MANE Select | |
| RefSeq | NP_001364221.1 | 4 | Standard | |
| RefSeq | NP_001364222.1 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- MAPK Signaling Pathway
- ESC Pluripotency Pathways
- Focal Adhesion-PI3K-Akt-mTOR-signaling pathway
- PI3K-Akt Signaling Pathway
- Regulation of Actin Cytoskeleton
Biological Process
- regulation of membrane depolarization
- signal transduction
- cell-cell signaling
- chemical synaptic transmission
- nervous system development
Molecular Function
- protein binding
- growth factor activity
- sodium channel regulator activity
- ion channel binding
Cellular Component
- extracellular space
- nucleus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000454309
- Coding exons
- 5
- Length
- 628370
- Individuals with no LoFs
- 125742
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 125746
- p
- 0.0000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.52 | 91 | 142 | 0.640 | 0.00000718 | 1571 |
| Missense (PolyPhen) | 16 | 46.389 | 0.34491 | 528 | ||
| Synonymous | 0.453 | 50 | 54.2 | 0.922 | 0.00000279 | 478 |
| Loss of Function | 2.63 | 2 | 11.7 | 0.171 | 5.83e-7 | 141 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.0000093 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in nervous system development and function. Involved in the positive regulation of voltage-gated sodium channel activity. Promotes neuronal excitability by elevating the voltage dependence of neuronal sodium channel SCN8A fast inactivation. {ECO:0000269|PubMed:27164707}.;
Recessive Scores
- pRec
- 0.174
Intolerance Scores
- LoFtool
- 0.209
- RVIS EVS
- -0.16
- RVIS percentile EVS
- 41.25
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.731
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |