FGF14

Summary

FGF14 (fibroblast growth factor 14, HGNC:3671) is a protein-coding gene on chromosome 13q33.1, encoding Fibroblast growth factor 14 (Q92915). Probably involved in nervous system development and function.

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. A mutation in this gene is associated with autosomal dominant cerebral ataxia. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 2259 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spinocerebellar ataxia 27A (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 12
• Clinical variants (ClinVar): 221 total — 18 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 34
• Druggable target: yes
• MANE Select transcript: NM_004115

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3671
Approved symbol	FGF14
Name	fibroblast growth factor 14
Location	13q33.1
Locus type	gene with protein product
Status	Approved
Aliases	FHF4, SCA27
Ensembl gene	ENSG00000102466
Ensembl biotype	protein_coding
OMIM	601515
Entrez	2259

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000376131, ENST00000376143, ENST00000418923, ENST00000468052, ENST00000706491, ENST00000706492, ENST00000706493, ENST00000706494

RefSeq mRNA: 21 — MANE Select: NM_004115 NM_001321931, NM_001321932, NM_001321933, NM_001321934, NM_001321935, NM_001321936, NM_001321938, NM_001321939, NM_001321940, NM_001321941, NM_001321942, NM_001321943, NM_001321944, NM_001321945, NM_001321946, NM_001321947, NM_001321948, NM_001321949, NM_001379342, NM_004115, NM_175929

CCDS: CCDS9500, CCDS9501

Canonical transcript exons

ENST00000376143 — 5 exons

Exon	Start	End
ENSE00000917061	101875186	101875296
ENSE00000998717	101726612	101726810
ENSE00000998720	101868725	101868828
ENSE00001469547	101916453	101916945
ENSE00001683243	101710804	101722967

Expression profiles

Bgee: expression breadth ubiquitous, 200 present calls, max score 99.75.

FANTOM5 (CAGE): breadth broad, TPM avg 3.6738 / max 832.5096, expressed in 248 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
138103	2.2945	211
138100	0.7347	115
138101	0.4406	98
138099	0.0939	49
138104	0.0720	42
138102	0.0290	12
207092	0.0091	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.75	gold quality
middle temporal gyrus	UBERON:0002771	97.42	gold quality
bronchial epithelial cell	CL:0002328	97.40	gold quality
oocyte	CL:0000023	96.93	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.96	gold quality
cerebellar vermis	UBERON:0004720	91.48	gold quality
epithelium of bronchus	UBERON:0002031	90.71	gold quality
endothelial cell	CL:0000115	90.47	gold quality
postcentral gyrus	UBERON:0002581	89.72	gold quality
superior frontal gyrus	UBERON:0002661	89.57	gold quality
entorhinal cortex	UBERON:0002728	89.54	gold quality
bronchus	UBERON:0002185	89.33	gold quality
primary visual cortex	UBERON:0002436	88.44	gold quality
parietal lobe	UBERON:0001872	87.83	gold quality
mucosa of paranasal sinus	UBERON:0005030	86.89	gold quality
cerebellum	UBERON:0002037	85.74	gold quality
occipital lobe	UBERON:0002021	85.32	gold quality
cerebellar cortex	UBERON:0002129	84.93	gold quality
cerebellar hemisphere	UBERON:0002245	84.64	gold quality
pons	UBERON:0000988	84.33	gold quality
Brodmann (1909) area 46	UBERON:0006483	83.94	gold quality
right hemisphere of cerebellum	UBERON:0014890	83.23	gold quality
prefrontal cortex	UBERON:0000451	82.64	gold quality
lateral nuclear group of thalamus	UBERON:0002736	82.17	gold quality
frontal cortex	UBERON:0001870	81.63	gold quality
heart right ventricle	UBERON:0002080	81.04	silver quality
neocortex	UBERON:0001950	80.35	gold quality
orbitofrontal cortex	UBERON:0004167	80.23	silver quality
calcaneal tendon	UBERON:0003701	79.97	gold quality
cerebral cortex	UBERON:0000956	79.66	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	5806.72
E-HCAD-25	yes	3901.68
E-CURD-114	yes	11.93
E-CURD-119	yes	10.08
E-ANND-3	yes	5.79
E-GEOD-83139	yes	4.42
E-GEOD-180759	no	4569.28
E-HCAD-30	no	4024.65
E-MTAB-5061	no	3.67

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

203 targeting FGF14, 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-3646	100.00	73.56	5283
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163

Literature-anchored findings (GeneRIF, showing 40)

• investigation of mutations in GCL modifier subunit and the GCL catalytic subunit that modify catalytic activity and lower glutathione levels (PMID:12954617)
• Neuronal overexpression of GCLc in a long-lived background extended mean and maximum life spans up to 50%, without affecting the rate of oxygen consumption by the flies (PMID:16148000)
• The reversibility of the dephosphorylation-dependent activation was indicated by the time-dependent inactivation of the in vitro activated Drosophila GCL, by preincubation with MgATP. (PMID:16324789)
• that the longevity effects of GCLc are dependent on dosage and that there are specific tissues (mushroom bodies, motor neurons, and transverse muscle cells) particularly sensitive to the benefits of GCLc overexpression. (PMID:18056974)
• GSH biosynthesis in the nucleus is associated with migration of only the GCLc subunit from the cytoplasm into the nucleus, and this migration requires the presence of an intact nuclear localization signal (PMID:19036725)
• Microarray analysis revealed that glutamate cysteine ligasec overexpression and thus enhanced glutathione production has a broad impact on gene expression that largely affects different processes in young and old flies. (PMID:22579812)
• we report phenotypic analysis of a complete loss-of-function mutant in the gamma-glutamylcysteine synthetase catalytic subunit (Gclc) gene in the fruit fly Drosophila melanogaster.Gclc encodes the evolutionarily conserved catalytic component of the enzyme that conjugates glutamate and cysteine in the GSH biosynthesis pathway. (PMID:29021278)
• A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebral ataxia (PMID:12489043)
• The gene NYS4 is associated with acquired vestibulocerebellar type nystagmus. (PMID:12525540)
• A G->A variant was found in a single spinocerebellar ataxia patient in the 3’ untranslated region, 31 bp to the STOP codon; it did not affect the polyadenylation site. FGF14 mutations are not a major cause of SCA in Caucasians. (PMID:15365159)
• Frameshift mutation and polymorphisms in the fibroblast growth factor 14 gene is associated with ataxias (PMID:15470364)
• these findings implicate FGF14 as a unique modulator of Nav channel activity in the CNS. (PMID:16166153)
• a distinct SCA (spinocerebellar ataxia)phenotype (SCA27) is associated with a F145S mutation in the fibroblast growth factor 14 (FGF14) gene on chromosome 13q34. (PMID:16211615)
• FGF14 mutations in Ataxia and childhood onset postural tremor. (PMID:17221845)
• THe present study demonstrates that Spinocerebellar ataxia type 27 (SCA27) caused by FGF14 mutation is rare in Chinese SCA patients. (PMID:22579694)
• inhibition of GSK3 reduces the assembly of the FGF14.Nav channel complex, modifies FGF14-dependent regulation of Na(+) currents, and induces dissociation and subcellular redistribution of the native FGF14.Nav channel complex in hippocampal neurons. (PMID:23640885)
• family demonstrates phenotypic variability of FGF14 deletions (SCA 27), fever sensitivity of ataxia and the added value of SNP-array analysis in making a diagnosis (PMID:24252256)
• study reports on a two-generation French Canadian family affected with autosomal dominant episodic ataxia caused by a frameshift mutation leading to a premature stop codon in FGF14 (PMID:25566820)
• identified the PI3K/Akt pathway, the cell-cycle regulator Wee1 kinase, and protein kinase C (PKC) as prospective regulatory nodes of neuronal excitability through modulation of the FGF14:Nav1.6 complex. (PMID:25659151)
• Either the FGF14(V160A) or the FGF14(K74A/I76A) mutation was sufficient to abolish the FGF14-dependent regulation of peak transient Na(+) currents and the voltage-dependent activation and steady-state inactivation of Nav1.6; but only V160A with a concomitant alanine mutation at Tyr-158 could impede FGF14-dependent modulation of the channel fast inactivation. (PMID:26994141)
• The data implicate FGF14 as an organizer of channel localization in the axon initial segment and provide insight into the coordination of KCNQ and voltage-gated sodium channel conductances in the regulation of membrane potential. (PMID:27994149)
• A novel nonsense mutation in FGF14 was identified in a patient with SCA27. (PMID:30017992)
• The findings uncovered the critical role of N(6)-methyladenosine in nasopharyngeal carcinoma (NPC), and stressed the regulatory function of the ZNF750-FGF14 signaling axis in modulating NPC progression, which provides theoretical guidance for the clinical treatment of NPC. (PMID:30518868)
• Long non-coding RNA FGF14-AS2 represses proliferation, migration, invasion, and induces apoptosis in breast cancer by sponging miR-205-5p. (PMID:31486497)
• Broader phenotypic traits and widespread brain hypometabolism in spinocerebellar ataxia 27. (PMID:32112487)
• A Variation in FGF14 Is Associated with Downbeat Nystagmus in a Genome-Wide Association Study. (PMID:32157568)
• FGF14-related episodic ataxia: delineating the phenotype of Episodic Ataxia type 9. (PMID:32162847)
• JAK2 regulates Nav1.6 channel function via FGF14(Y158) phosphorylation. (PMID:32599005)
• Mapping of the FGF14:Nav1.6 complex interface reveals FLPK as a functionally active peptide modulating excitability. (PMID:32671946)
• Fibroblast Growth Factor-14 Acts as Tumor Suppressor in Lung Adenocarcinomas. (PMID:32707902)
• MEX3C promotes osteosarcoma malignant progression through negatively regulating FGF14. (PMID:32862604)
• Genomic relevance of FGF14 and associated genes on the prognosis of pancreatic cancer. (PMID:34061869)
• An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14. (PMID:36493768)
• Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. (PMID:36516086)
• GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response. (PMID:37165652)
• Shaking Up Ataxia: FGF14 and RFC1 Repeat Expansions in Affected and Unaffected Members of a Chilean Family. (PMID:37246629)
• Optimized testing strategy for the diagnosis of GAA-FGF14 ataxia/spinocerebellar ataxia 27B. (PMID:37322040)
• Intronic FGF14 GAA repeat expansions are a common cause of ataxia syndromes with neuropathy and bilateral vestibulopathy. (PMID:37399286)
• Natural History and Phenotypic Spectrum of GAA-FGF14 Sporadic Late-Onset Cerebellar Ataxia (SCA27B). (PMID:37470282)
• Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan. (PMID:37916889)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fgf14	ENSDARG00000040982
mus_musculus	Fgf14	ENSMUSG00000025551
rattus_norvegicus	Fgf14	ENSRNOG00000009288

Paralogs (21): FGF10 (ENSG00000070193), FGF22 (ENSG00000070388), FGF4 (ENSG00000075388), FGF20 (ENSG00000078579), FGF9 (ENSG00000102678), FGF21 (ENSG00000105550), FGF8 (ENSG00000107831), FGF6 (ENSG00000111241), FGF1 (ENSG00000113578), FGF12 (ENSG00000114279), FGF23 (ENSG00000118972), FGF13 (ENSG00000129682), FGF5 (ENSG00000138675), FGF2 (ENSG00000138685), FGF7 (ENSG00000140285), FGF18 (ENSG00000156427), FGF17 (ENSG00000158815), FGF11 (ENSG00000161958), FGF19 (ENSG00000162344), FGF3 (ENSG00000186895), FGF16 (ENSG00000196468)

Protein

Protein identifiers

Fibroblast growth factor 14 — Q92915 (reviewed: Q92915)

Alternative names: Fibroblast growth factor homologous factor 4

All UniProt accessions (7): Q92915, A0A7U3JVZ8, A0A9L9PWZ4, A0A9L9PX77, A0A9L9PXI9, A0A9L9PXK7, A0A9L9PY24

UniProt curated annotations — full annotation on UniProt →

Function. Probably involved in nervous system development and function.

Subunit / interactions. Interacts with SCN8A.

Subcellular location. Nucleus.

Tissue specificity. Nervous system.

Disease relevance. Spinocerebellar ataxia 27A (SCA27A) [MIM:193003] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA27A is an autosomal dominant, slowly progressive form characterized by gait disturbances, ataxia with tremor, dysarthria, orofacial dyskinesia, gaze-evoked nystagmus, and learning disabilities. There is significant variability, and patients show various combinations of neurologic features. The disease is caused by variants affecting the gene represented in this entry. Spinocerebellar ataxia 27B, late-onset (SCA27B) [MIM:620174] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA27B is an autosomal dominant, slowly progressive form characterized by the onset of gait and appendicular ataxia in adulthood. The disease is caused by variants affecting the gene represented in this entry. SCA27B is caused by GAA(n) trinucleotide repeat expansions with a size above 250 repeats in FGF14 intron 1. Expansions ranging from 250 to 300 repeats are pathogenic albeit with reduced penetrance, whereas those above 300 are fully penetrant.

Similarity. Belongs to the heparin-binding growth factors family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92915-1	1	yes
Q92915-2	2, Isoform 1B

RefSeq proteins (21): NP_001308860, NP_001308861, NP_001308862, NP_001308863, NP_001308864, NP_001308865, NP_001308867, NP_001308868, NP_001308869, NP_001308870, NP_001308871, NP_001308872, NP_001308873, NP_001308874, NP_001308875, NP_001308876, NP_001308877, NP_001308878, NP_001366271, NP_004106, NP_787125 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002209	Fibroblast_GF_fam	Family
IPR008996	IL1/FGF	Homologous_superfamily

Pfam: PF00167

UniProt features (9 total): sequence variant 4, region of interest 2, chain 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92915-F1	79.77	0.60

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5576892	Phase 0 - rapid depolarisation

MSigDB gene sets: 298 (showing top): KEGG_MAPK_SIGNALING_PATHWAY, GOBP_NEUROGENESIS, GOMF_GROWTH_FACTOR_ACTIVITY, FOXO4_01, FOXO1_01, USF_C, CAGCTG_AP4_Q5, TTGCWCAAY_CEBPB_02, CEBPB_01, GOBP_CELL_CELL_SIGNALING, AACWWCAANK_UNKNOWN, CEBP_Q2, CATRRAGC_UNKNOWN, KEGG_PATHWAYS_IN_CANCER, MYCMAX_01

GO Biological Process (5): signal transduction (GO:0007165), JNK cascade (GO:0007254), cell-cell signaling (GO:0007267), nervous system development (GO:0007399), neurogenesis (GO:0022008)

GO Molecular Function (4): growth factor activity (GO:0008083), heparin binding (GO:0008201), sodium channel regulator activity (GO:0017080), protein binding (GO:0005515)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cardiac conduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	2
signaling	2
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
MAPK cascade	1
system development	1
nervous system development	1
cell differentiation	1
receptor ligand activity	1
glycosaminoglycan binding	1
sulfur compound binding	1
sodium channel activity	1
ion channel regulator activity	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1612 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FGF14	SCN8A	Q9UQD0	886
FGF14	MAPK8IP2	Q13387	711
FGF14	SCN2A	Q99250	703
FGF14	FGF17	O60258	683
FGF14	FGF18	O76093	681
FGF14	FGFR2	P18443	651
FGF14	RAP2A	P10114	640
FGF14	KCNC3	Q14003	628
FGF14	FGF8	P55075	627
FGF14	SPTBN2	O15020	610
FGF14	TTBK2	Q6IQ55	572
FGF14	FGFR1	P11362	572
FGF14	ATXN10	Q9UBB4	570
FGF14	APOD	P05090	567
FGF14	CACNA1A	P78510	544

IntAct

19 interactions, top by confidence:

A	B	Type	Score
APP	FGF14	psi-mi:“MI:0915”(physical association)	0.560
H3C1	FGF14	psi-mi:“MI:0915”(physical association)	0.370
FGF14	NOLC1	psi-mi:“MI:0914”(association)	0.350
FGF14	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
FGF14	ANKRD28	psi-mi:“MI:0914”(association)	0.350
AKT1	FGF14	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	FGF14	psi-mi:“MI:2364”(proximity)	0.270
SPOP	FGF14	psi-mi:“MI:2364”(proximity)	0.270
FGF14	SPOP	psi-mi:“MI:2364”(proximity)	0.270
EGFR	FGF14	psi-mi:“MI:2364”(proximity)	0.270
FGF14	PTEN	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (44): SCN8A (Reconstituted Complex), SCN8A (Affinity Capture-Luminescence), SCN8A (Affinity Capture-Western), FGF14 (Two-hybrid), FGF14 (Two-hybrid), FKBP8 (Two-hybrid), EHHADH (Two-hybrid), TTPA (Two-hybrid), SYT16 (Two-hybrid), FUNDC2 (Two-hybrid), HOXD12 (Two-hybrid), FBXO34 (Two-hybrid), RTP5 (Two-hybrid), HIST1H4G (Two-hybrid), ACACA (Two-hybrid)

ESM2 similar proteins: A6P7H6, O35622, O57341, O76093, O88182, O89101, P03968, P03969, P12226, P13109, P15655, P19596, P20003, P21781, P36363, P37237, P41444, P48798, P48800, P48808, P61150, P61328, P61329, P70377, P70378, P70379, P79150, Q02195, Q0VCA0, Q5D0X0, Q5MK86, Q5MPA9, Q5RAY8, Q5RDS9, Q60487, Q6DTM3, Q6GLR6, Q6PGN3, Q6SJP8, Q7M303

Diamond homologs: A0MTF4, A6P7H6, M3X9S6, O15520, O35565, O43320, O54769, P03968, P03969, P05230, P05524, P08620, P09038, P10767, P11403, P11487, P12034, P12226, P13109, P15655, P15656, P19596, P20002, P20003, P21658, P21781, P31371, P34004, P36363, P36364, P36386, P48798, P48799, P48800, P48801, P48802, P48803, P48804, P48805, P48806

SIGNOR signaling

19 interactions.

A	Effect	B	Mechanism
FGF14	“down-regulates activity”	SCN8A	binding
FGF14	“down-regulates activity”	SCN5A	binding
FGF14	“down-regulates activity”	SCN1A	binding
FGF14	“down-regulates activity”	SCN9A	binding
FGF14	“down-regulates activity”	SCN2A	binding
FGF14	“down-regulates activity”	SCN4A	binding
FGF14	“down-regulates activity”	SCN11A	binding
FGF14	“down-regulates activity”	SCN10A	binding
FGF14	“down-regulates activity”	SCN3A	binding
CSNK2A1	“up-regulates activity”	FGF14	phosphorylation
CSNK2A2	“up-regulates activity”	FGF14	phosphorylation
CSNK2A3	“up-regulates activity”	FGF14	phosphorylation
CSNK2B	“up-regulates activity”	FGF14	phosphorylation
GSK3B	“up-regulates activity”	FGF14	phosphorylation
JAK2	“up-regulates activity”	FGF14	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	8
Uncertain significance	109
Likely benign	36
Benign	29

Top pathogenic / likely-pathogenic (26)

Variant ID	HGVS	Classification
1070863	NC_000013.10:g.(?102029051)(103054028_?)del	Pathogenic
1694709	NM_004115.4(FGF14):c.439G>T (p.Glu147Ter)	Pathogenic
1704305	GRCh37/hg19 13q33.1(chr13:102535482-102815349)x3	Pathogenic
1710296	NM_175929.3(FGF14):c.208+239747CTT[349]	Pathogenic
1710304	NM_004115.4(FGF14):c.211dup (p.Ile71fs)	Pathogenic
1806479	NG_008317.3:g.245717TTC[250_?]	Pathogenic
1806675	NM_004115.4(FGF14):c.305-2A>G	Pathogenic
2425024	NC_000013.10:g.(?102521055)(102568995_?)del	Pathogenic
2430157	NM_175929.3(FGF14):c.208+239747CTT[250]	Pathogenic
3024582	GRCh37/hg19 13q33.1(chr13:102105185-102379160)x1	Pathogenic
3061913	NM_004115.4(FGF14):c.512G>A (p.Trp171Ter)	Pathogenic
4813514	NM_004115.4(FGF14):c.353G>T (p.Gly118Val)	Pathogenic
489406	NM_004115.4(FGF14):c.529A>T (p.Lys177Ter)	Pathogenic
59858	GRCh38/hg38 13q12.11-34(chr13:18946182-114304628)x3	Pathogenic
687082	GRCh37/hg19 13q33.1(chr13:102139098-102392931)x1	Pathogenic
8115	NM_004115.4(FGF14):c.434T>C (p.Phe145Ser)	Pathogenic
8116	NM_004115.4(FGF14):c.487del (p.Arg163fs)	Pathogenic
976772	GRCh37/hg19 13q33.1(chr13:102521075-102568995)	Pathogenic
1723288	NM_004115.4(FGF14):c.408+1G>A	Likely pathogenic
2300494	NM_004115.4(FGF14):c.409-1245_464del	Likely pathogenic
3064124	NM_004115.4(FGF14):c.194-1G>C	Likely pathogenic
3346214	NM_004115.4(FGF14):c.438_466del (p.Lys146fs)	Likely pathogenic
4291811	NM_004115.4(FGF14):c.162_184del (p.Phe54fs)	Likely pathogenic
560058	Single allele	Likely pathogenic
564045	GRCh37/hg19 13q33.1(chr13:101956482-102666953)x1	Likely pathogenic
598976	NM_004115.4(FGF14):c.486dup (p.Arg163fs)	Likely pathogenic

SpliceAI

2490 predictions. Top by Δscore:

Variant	Effect	Δscore
13:101726607:CTCA:C	donor_loss	1.0000
13:101726608:TCACC:T	donor_loss	1.0000
13:101726609:CAC:C	donor_loss	1.0000
13:101726610:A:AC	donor_gain	1.0000
13:101726611:C:CC	donor_gain	1.0000
13:101726611:CCTT:C	donor_gain	1.0000
13:101875184:A:AC	donor_gain	1.0000
13:101875185:C:CC	donor_gain	1.0000
13:101916474:T:TA	donor_gain	1.0000
13:101722968:C:CC	acceptor_gain	0.9900
13:101726610:AC:A	donor_gain	0.9900
13:101726610:ACCTT:A	donor_gain	0.9900
13:101726611:CC:C	donor_gain	0.9900
13:101726611:CCTTC:C	donor_gain	0.9900
13:101726808:TTCCT:T	acceptor_loss	0.9900
13:101726809:TCCTG:T	acceptor_loss	0.9900
13:101726811:C:CA	acceptor_loss	0.9900
13:101726811:C:CC	acceptor_gain	0.9900
13:101726812:T:A	acceptor_loss	0.9900
13:101742918:C:CC	acceptor_gain	0.9900
13:101868723:A:AC	donor_gain	0.9900
13:101868724:C:CC	donor_gain	0.9900
13:101874775:T:TA	donor_gain	0.9900
13:101916451:A:AT	donor_loss	0.9900
13:101916452:CCTTG:C	donor_loss	0.9900
13:101916494:A:AC	donor_gain	0.9900
13:101916495:C:CC	donor_gain	0.9900
13:101715557:TTGCA:T	acceptor_loss	0.9800
13:101715558:TGCAG:T	acceptor_loss	0.9800
13:101715559:GCA:G	acceptor_loss	0.9800

AlphaMissense

1616 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:101726631:A:C	F196L	1.000
13:101726631:A:T	F196L	1.000
13:101726632:A:G	F196S	1.000
13:101726633:A:G	F196L	1.000
13:101726638:G:T	A194D	1.000
13:101726668:C:T	G184E	1.000
13:101726669:C:A	G184W	1.000
13:101726669:C:G	G184R	1.000
13:101726669:C:T	G184R	1.000
13:101726698:C:T	G174E	1.000
13:101726699:C:G	G174R	1.000
13:101726699:C:T	G174R	1.000
13:101726708:A:G	W171R	1.000
13:101726708:A:T	W171R	1.000
13:101726712:T:A	R169S	1.000
13:101726712:T:G	R169S	1.000
13:101726743:G:A	S159F	1.000
13:101726750:A:C	Y157D	1.000
13:101726773:A:T	V149D	1.000
13:101726777:A:G	S148P	1.000
13:101726781:T:A	K146N	1.000
13:101726781:T:G	K146N	1.000
13:101726785:A:G	F145S	1.000
13:101726790:G:C	C143W	1.000
13:101726792:A:G	C143R	1.000
13:101868741:C:A	G131V	1.000
13:101868741:C:T	G131D	1.000
13:101868742:C:G	G131R	1.000
13:101868783:T:G	Q117P	1.000
13:101868790:C:G	A115P	1.000

dbSNP variants (sampled 300 via entrez): RS1000000894 (13:102275252 C>T), RS1000001024 (13:101976358 A>G), RS1000001695 (13:102320503 G>A), RS1000004289 (13:101779591 T>C), RS1000015215 (13:101859145 A>T), RS1000017712 (13:102350432 T>C), RS1000021977 (13:102098076 A>T), RS1000023205 (13:101940680 T>G), RS1000024222 (13:102181157 C>A), RS1000027517 (13:102005332 T>C), RS1000027652 (13:101884904 T>C), RS1000031742 (13:102054208 G>A), RS1000031932 (13:102391264 T>C), RS1000032342 (13:102083105 A>G), RS1000032792 (13:102215948 T>A)

Disease associations

OMIM: gene MIM:601515 | disease phenotypes: MIM:193003, MIM:609307, MIM:620174

GenCC curated gene-disease

Disease	Classification	Inheritance
spinocerebellar ataxia type 27	Strong	Autosomal dominant
spinocerebellar ataxia 27A	Strong	Autosomal dominant
autosomal recessive cerebellar ataxia	Limited	Autosomal recessive

Mondo (5): spinocerebellar ataxia 27A (MONDO:0008654), spinocerebellar ataxia type 27 (MONDO:0012247), cerebellar ataxia (MONDO:0000437), spinocerebellar ataxia 27B, late-onset (MONDO:0859340), autosomal recessive cerebellar ataxia (MONDO:0015244)

Orphanet (3): Spinocerebellar ataxia type 27A (Orphanet:98764), Rare ataxia (Orphanet:102002), Spinocerebellar ataxia type 27B (Orphanet:675216)

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000486	Strabismus
HP:0000640	Gaze-evoked nystagmus
HP:0000642	Red-green dyschromatopsia
HP:0000651	Diplopia
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0001256	Mild intellectual disability
HP:0001260	Dysarthria
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001337	Tremor
HP:0001761	Pes cavus
HP:0002066	Gait ataxia
HP:0002070	Limb ataxia
HP:0002078	Truncal ataxia
HP:0002174	Postural tremor
HP:0002304	Akinesia
HP:0002310	Orofacial dyskinesia
HP:0002321	Vertigo
HP:0002354	Memory impairment
HP:0002378	Hand tremor
HP:0002495	Impaired vibratory sensation
HP:0003390	Sensory axonal neuropathy
HP:0003581	Adult onset
HP:0003680	Nonprogressive
HP:0007179	Absent smooth pursuit
HP:0007670	Abnormal vestibulo-ocular reflex
HP:0007772	Impaired smooth pursuit
HP:0007979	Gaze-evoked horizontal nystagmus

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST000903_4	Response to methylphenidate treatment in attention-deficit/hyperactivity disorder (blood pressure)	6.000000e-06
GCST001949_1	Preeclampsia	7.000000e-07
GCST002347_3	Response to protease inhibitor treatment in hepatitis c (bilirubin toxicity)	8.000000e-06
GCST004764_6	LDL cholesterol change in response to fenofibrate in statin-treated type 2 diabetes	4.000000e-07
GCST004765_10	Total cholesterol change in response to fenofibrate in statin-treated type 2 diabetes	1.000000e-07
GCST006431_18	Plasma parathyroid hormone levels	2.000000e-06
GCST006444_6	Bone mineral density (hip)	5.000000e-07
GCST008675_5	Maximum habitual alcohol consumption	1.000000e-08
GCST010172_10	Idiopathic downbeat nystagmus	2.000000e-08
GCST010320_93	PR interval	1.000000e-09
GCST010321_81	PR interval	2.000000e-11
GCST012489_60	Heel bone mineral density x serum urate levels interaction	3.000000e-08

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004570	bilirubin measurement
EFO:0005657	response to protease inhibitor
EFO:0007804	LDL cholesterol change measurement
EFO:0007806	total cholesterol change measurement
EFO:0007702	hip bone mineral density
EFO:0004462	PR interval
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
C537204	Spinocerebellar ataxia 27 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4523624 (PROTEIN-PROTEIN INTERACTION), CHEMBL4739699 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs75805413	FGF14		0.00	0

Binding affinities (BindingDB)

7 measured of 7 human assays (7 total across all organisms); most potent 7 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL4762315	KD	1310 nM
CHEMBL4758370	KD	4050 nM
CHEMBL4778774	KD	6940 nM
CHEMBL4787949	KD	7020 nM
CHEMBL4792323	KD	9470 nM
CHEMBL4745065	KD	11400 nM
CHEMBL4784008	KD	14700 nM

ChEMBL bioactivities

6 potent at pChembl≥5 of 10 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.88	Kd	1310	nM	CHEMBL4762315
5.85	Kd	1419	nM	CHEMBL4758370
5.39	Kd	4050	nM	CHEMBL4758370
5.16	Kd	6940	nM	CHEMBL4778774
5.15	Kd	7020	nM	CHEMBL4787949
5.02	Kd	9470	nM	CHEMBL4792323

PubChem BioAssay actives

6 with measured affinity, of 55 total; 5 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
tert-butyl (4S)-4-[[(2S)-2-[[(2S)-1-(adamantane-1-carbonyl)pyrrolidine-2-carbonyl]amino]-4-methylpentanoyl]amino]-5-[[(2S)-3-methyl-1-oxo-1-prop-2-enoxybutan-2-yl]amino]-5-oxopentanoate	1698888: Binding affinity to human recombinant FGF14 expressed in Escherichia coli BL21 assessed as dissociation constant by SPR analysis	kd	1.3100	uM
tert-butyl (4S)-4-[[(2S)-2-[[(2S)-1-(adamantane-1-carbonyl)pyrrolidine-2-carbonyl]amino]-4-methylpentanoyl]amino]-5-[[(2S)-1-methoxy-3-methyl-1-oxobutan-2-yl]amino]-5-oxopentanoate	1698894: Modulation of human recombinant FGF14-Nav1.6 C-terminal domain expressed in Escherichia coli BL21 (DE3) protein-protein interaction assessed as dissociation constant by SPR analysis (Rvb = 228.5 +/- 57.54 nM)	kd	1.4186	uM
tert-butyl (4S)-4-[[(2S)-2-[[(2S)-1-(adamantane-1-carbonyl)pyrrolidine-2-carbonyl]amino]-4-methylpentanoyl]amino]-5-[[(2S)-3-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxobutan-2-yl]amino]-5-oxopentanoate	1698888: Binding affinity to human recombinant FGF14 expressed in Escherichia coli BL21 assessed as dissociation constant by SPR analysis	kd	6.9400	uM
tert-butyl (4S)-4-[[(2S)-2-[[(2S)-1-(adamantane-1-carbonyl)pyrrolidine-2-carbonyl]amino]-4-methylpentanoyl]amino]-5-[[(2S)-1-cyclohexyloxy-3-methyl-1-oxobutan-2-yl]amino]-5-oxopentanoate	1698888: Binding affinity to human recombinant FGF14 expressed in Escherichia coli BL21 assessed as dissociation constant by SPR analysis	kd	7.0200	uM
tert-butyl (4S)-4-[[(2S)-2-[[(2S)-1-(adamantane-1-carbonyl)pyrrolidine-2-carbonyl]amino]-4-methylpentanoyl]amino]-5-[[(2S)-1-ethoxy-3-methyl-1-oxobutan-2-yl]amino]-5-oxopentanoate	1698888: Binding affinity to human recombinant FGF14 expressed in Escherichia coli BL21 assessed as dissociation constant by SPR analysis	kd	9.4700	uM

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	3
Valproic Acid	decreases methylation, increases expression, affects expression	3
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	affects methylation, decreases methylation	2
securinine	decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	increases methylation	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	decreases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
abrine	increases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
bisphenol S	increases methylation	1
Arsenic Trioxide	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Lead	affects expression	1
Methapyrilene	increases methylation	1
Nickel	decreases expression	1
Phthalic Acids	decreases methylation	1
Rotenone	affects expression	1
Tobacco Smoke Pollution	decreases expression	1
Cyclosporine	increases expression	1
Antirheumatic Agents	decreases expression	1

ChEMBL screening assays

16 unique, capped per target: 16 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4332053	Binding	Modulation of Cluc-FGF14 (unknown origin)/CD4-Nav1.6-Nluc (unknown origin) protein-protein interaction using FGF14/NAV1.6 using HEK293 cells expressing FGF14/Nav1.6 assessed as luminescent response at 50 uM by split luciferase complementati	Identification of peptidomimetics as novel chemical probes modulating fibroblast growth factor 14 (FGF14) and voltage-gated sodium channel 1.6 (Nav1.6) protein-protein interactions. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D8GC	Ubigene H9 FGF14 KO	Embryonic stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT04107740	PHASE4	COMPLETED	C-Trelin Orally Disintegrated(OD) Tablet 5mg in Ataxia Due to Spinocerebellar Degeneration
NCT01970098	PHASE3	COMPLETED	A Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970111	PHASE3	COMPLETED	An Extension Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970124	PHASE3	COMPLETED	A Long-Term Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970137	PHASE3	COMPLETED	A 24-week Open-label Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT02889302	PHASE3	COMPLETED	An Additional Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT03901638	PHASE3	TERMINATED	Tllsh2910 for Ataxia and Gut Microbiota Alteration in Patients of Multiple System Atrophy
NCT07040137	PHASE3	RECRUITING	Confirmatory Study 3 of KPS-0373 in Patients With Spinocerebellar Degeneration
NCT00034242	PHASE2	COMPLETED	High-Dose Intravenous Immunoglobulin to Treat Cerebellar Degeneration
NCT00202397	PHASE2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia
NCT00863538	PHASE2	COMPLETED	Phase II Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01004016	PHASE2	COMPLETED	A Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01350440	PHASE2	COMPLETED	Safety and Efficacy of Intravenous Immune Globulin in Treating Spinocerebellar Ataxia
NCT02540655	PHASE2	COMPLETED	Efficacy and Safety Study of Stemchymal® in Polyglutamine Spinocerebellar Ataxia
NCT03932669	PHASE2	COMPLETED	Effect of Nilotinib in Cerebellar Ataxia Patients
NCT04301284	PHASE2	WITHDRAWN	Study of CAD-1883 for Spinocerebellar Ataxia
NCT05125666	PHASE2	UNKNOWN	Efficacy of Dual Task Training on Children With Ataxia After Medulloblastoma Resection
NCT06397274	PHASE2	NOT_YET_RECRUITING	Stemchymal® for Polyglutamine Spinocerebellar Ataxia
NCT00683943	PHASE1	COMPLETED	Lithium Treatment for Patients With Spinocerebellar Ataxia Type I
NCT02287064	PHASE1	UNKNOWN	An Open-label Trial of Intravenous Immune Globulin (IVIG)in Treating Spinocerebellar Ataxias
NCT05157802	PHASE1	ACTIVE_NOT_RECRUITING	Promoting Physical Activity Engagement for People With Early-stage Cerebellar Ataxia
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT04261127	Not specified	RECRUITING	Validation of the RADIAL Algorithm for Diagnosis of Autosomal Recessive Cerebellar Ataxia
NCT01104649	PHASE2/PHASE3	COMPLETED	Efficacy of Riluzole in Hereditary Cerebellar Ataxia
NCT02960893	PHASE2/PHASE3	COMPLETED	Trial in Adult Participants With Spinocerebellar Ataxia (SCA)
NCT00244361	PHASE1/PHASE2	COMPLETED	Effectiveness of Rituximab in Pediatric OMS Patients.
NCT01649687	PHASE1/PHASE2	COMPLETED	Treatment of Cerebellar Ataxia With Mesenchymal Stem Cells
NCT01958177	PHASE1/PHASE2	UNKNOWN	Clinical Study to Evaluate the Safety and Efficacy BMMNC in Cerebellar Ataxia
NCT02829268	PHASE1/PHASE2	COMPLETED	A Clinical Trial of Dantrolene Sodium in Pediatric and Adult Patients With Wolfram Syndrome
NCT00001324	Not specified	COMPLETED	PET Scan to Study Brain Control of Human Movement
NCT00006492	Not specified	COMPLETED	Gluten-Free Diet in Patients With Gluten Sensitivity and Cerebellar Ataxia
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00272272	Not specified	COMPLETED	Fall Prevention in a Geriatric Nursing Home Setting Using the Music of Nolwenn Leroy
NCT00654251	Not specified	COMPLETED	Measuring Neurological Impairment and Functional Visual Assessment In Spinocerebellar Ataxias
NCT00692861	Not specified	COMPLETED	Autoimmunity in Neurologic Complications of Celiac Disease
NCT01037777	Not specified	COMPLETED	RISCA : Prospective Study of Individuals at Risk for SCA1, SCA2, SCA3, SCA6, SCA7