PFN1

Summary

PFN1 (profilin 1, HGNC:8881) is a protein-coding gene on chromosome 17p13.2, encoding Profilin-1 (P07737). Binds to actin and affects the structure of the cytoskeleton. It is a selective cancer dependency (DepMap: 79.5% of cell lines).

This gene encodes a member of the profilin family of small actin-binding proteins. The encoded protein plays an important role in actin dynamics by regulating actin polymerization in response to extracellular signals. Deletion of this gene is associated with Miller-Dieker syndrome, and the encoded protein may also play a role in Huntington disease. Multiple pseudogenes of this gene are located on chromosome 1.

Source: NCBI Gene 5216 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amyotrophic lateral sclerosis type 18 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 103 total — 3 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 49
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 79.5% of screened cell lines
• MANE Select transcript: NM_005022

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8881
Approved symbol	PFN1
Name	profilin 1
Location	17p13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000108518
Ensembl biotype	protein_coding
OMIM	176610
Entrez	5216

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 11 protein_coding

ENST00000225655, ENST00000572383, ENST00000574872, ENST00000896490, ENST00000896491, ENST00000896492, ENST00000896493, ENST00000896494, ENST00000929512, ENST00000929513, ENST00000929514

RefSeq mRNA: 2 — MANE Select: NM_005022 NM_001375991, NM_005022

CCDS: CCDS11061

Canonical transcript exons

ENST00000225655 — 3 exons

Exon	Start	End
ENSE00000676461	4946628	4946820
ENSE00001324890	4948263	4948530
ENSE00001488299	4945652	4945997

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 99.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1089.4594 / max 7434.4493, expressed in 1828 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
163981	839.4198	1828
163982	235.4123	1828
163985	7.4911	1694
163984	5.4445	1628
163983	0.5098	264
163980	0.4662	223
163986	0.4146	202
163979	0.3010	87

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.89	gold quality
mucosa of transverse colon	UBERON:0004991	99.86	gold quality
ileal mucosa	UBERON:0000331	99.79	gold quality
lower esophagus	UBERON:0013473	99.79	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.79	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.79	gold quality
monocyte	CL:0000576	99.77	gold quality
leukocyte	CL:0000738	99.77	gold quality
ascending aorta	UBERON:0001496	99.77	gold quality
thoracic aorta	UBERON:0001515	99.77	gold quality
mononuclear cell	CL:0000842	99.76	gold quality
stromal cell of endometrium	CL:0002255	99.76	gold quality
transverse colon	UBERON:0001157	99.76	gold quality
descending thoracic aorta	UBERON:0002345	99.76	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.76	gold quality
metanephros cortex	UBERON:0010533	99.75	gold quality
left coronary artery	UBERON:0001626	99.74	gold quality
aorta	UBERON:0000947	99.73	gold quality
vermiform appendix	UBERON:0001154	99.72	gold quality
sigmoid colon	UBERON:0001159	99.72	gold quality
right coronary artery	UBERON:0001625	99.72	gold quality
popliteal artery	UBERON:0002250	99.72	gold quality
small intestine Peyer’s patch	UBERON:0003454	99.72	gold quality
tibial artery	UBERON:0007610	99.72	gold quality
spleen	UBERON:0002106	99.70	gold quality
body of uterus	UBERON:0009853	99.70	gold quality
left uterine tube	UBERON:0001303	99.69	gold quality
coronary artery	UBERON:0001621	99.69	gold quality
smooth muscle tissue	UBERON:0001135	99.68	gold quality
upper lobe of left lung	UBERON:0008952	99.67	gold quality

Single-cell (SCXA)

Detected in 52 experiment(s), a significant marker in 27.

Experiment	Marker?	Max mean expression
E-MTAB-9467	yes	5427.00
E-MTAB-10662	yes	4643.26
E-CURD-97	yes	4377.65
E-MTAB-10042	yes	4267.58
E-CURD-46	yes	2308.12
E-MTAB-9221	yes	2031.65
E-MTAB-10855	yes	2005.54
E-MTAB-10283	yes	1956.74
E-MTAB-9543	yes	1711.33
E-MTAB-6678	yes	1504.15
E-MTAB-11011	yes	1316.33
E-HCAD-4	yes	164.74
E-HCAD-1	yes	139.06
E-MTAB-10287	yes	71.73
E-CURD-122	yes	54.23

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT3

miRNA regulators (miRDB)

45 targeting PFN1, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-7155-3P	99.57	66.48	794
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-224-3P	98.91	68.42	1815
HSA-MIR-522-3P	98.91	68.56	1817

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 79.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Mutational analysis of profilin I reveals a second phosphatidylinositol 4,5-bisphosphate binding site neighbouring the poly(L-proline) binding site. (PMID:12052260)
• two interaction regions for phosphatidylinositol(4,5)-bisphoaphate on human profilin I. (PMID:12095630)
• Data show that profilin antibodies interfere with pre-mRNA splicing in vitro, indicating a role for profilin during pre-mRNA processing. (PMID:12729790)
• tumor suppressor function of PFN1 requires a functional actin binding site (PMID:14767055)
• Taken together, our data show the importance of the interaction of profilin I with actin, proline-rich proteins and phosphatidylinositol 4,5-bisphosphate in neuronal differentiation of PC12 cells. (PMID:16569658)
• Profilin-1 may play important role in biological events that involve endothelial proliferation, migration and morphogenesis. (PMID:16968742)
• Overexpression of PFN1 led to inhibition of cell proliferation and migration. PFN1 knockdown could rescue the inhibitory effect of ATRA on cell proliferation and migration. ATRA inhibited cell proliferation and migration through up-regulation of PFN1. (PMID:17051635)
• analysis of the structural basis of profilin-actin complexes during filament elongation by Ena/VASP (PMID:17914456)
• The overexpressed Pfn1 must have a functional actin-binding site to suppress cell motility and animal experiments reveal that overexpression of Pfn1 suppresses orthotopic tumorigenicity and micro-metastasis of MDA-MB-231 cells in nude mice. (PMID:17940506)
• Profilin controls the energetics of its interaction with nonhybrid actin, but interactions between actin subdomains 1 and 2 affect the topography of the profilin binding site. (PMID:18223293)
• adenosine triphosphate synthase alpha chain was up-regulated, whereas annexin II, annexin V, beta(2)-tubulin, and profilin 1 were down-regulated in nasopharyngeal cancer cell lines (PMID:18384219)
• Overexpression of profilin abolishes mutant huntingtin toxicity in cells and partially ameliorates the morphological and functional eye phenotype and extends lifespan in a transgenic polyglutamine Drosophila model. (PMID:18417352)
• A signaling pathway from ROCK1 to profilin controls polyglutamine protein aggregation. (PMID:18573880)
• most likely hypotheses to explain the incompatibility of human profilin-I with Cdc12p are differences in interactions with the proline-rich sequences in the FH1 domain of Cdc12p and wider “wings” that interact with actin (PMID:19028693)
• NMR analysis of the binding between human profilin I and inositol 1,4,5-triphosphate (PMID:19035654)
• Data demonstrate that profilin-1 downregulation results in a hyper-motile phenotype of MDA-MB-231 breast cancer cells in an Ena/VASP-dependent mechanism. (PMID:19115233)
• important role of Pfn1 in the regulation of epithelial cell-cell adhesion (PMID:19593789)
• PFN1 regulates vascular endothelial cell migration, invasion and capillary morphogenesis by its interaction with actin and proline-rich ligands. (PMID:19607826)
• Results suggest that actin acts as a classical transcription factor for the virus by divalent-cation-dependent binding to the viral template and that profilin acts as a transcriptional cofactor, in part by associating with actin. (PMID:19710142)
• Pfn1 overexpression results in increased protein stability of p27(kip1) (p27-a major cyclin-dependent kinase inhibitor) and marked elevation in the overall cellular level of p27. (PMID:20143334)
• Profilin 1 induces vascular hypertrophy in resistance vessels, which leads to elevation of blood pressure, both of which contribute to the modulation of vascular function. (PMID:20400688)
• *ata demonstrate that PGE(2) partially stimulates hMSCs migration and proliferation by interaction of Pfn-1 and F-actin via EP2 receptor-dependent beta-arrestin-1/JNK signaling pathways. (PMID:20717968)
• data indicate that profilin-1 might critically contribute to atherogenesis and may represent a novel therapeutic target (PMID:21049052)
• potential to serve as a diagnostic or progression biomarker and therapeutic target in renal cell carcinoma (PMID:21091798)
• Data show that profilin1 negatively regulates lamellipodin targeting to the leading edge; profilin1 depletion increases lamellipodin concentration at the lamellipodial tip (where it binds Ena/VASP), and this mediates the hypermotility. (PMID:21115820)
• IgE recognition profile of profilins, PR-10 proteins and tropomyosin, were evaluated. (PMID:21949785)
• By tissue microarray, profilin 1 expression was markedly decreased in epithelial cells of the invasive versus high risk non invasive bladder tumors; this pattern is strongly correlated with poor prognosis and increased mortality (PMID:22159600)
• Data show that calreticulin and profilin-1 are differentially expressed after poly(I:C) treatment, and that calreticulin expression might be Toll-like receptor 3 (TLR3) dependent by using TLR3 small interfering RNA. (PMID:22415225)
• mutations within the profilin 1 (PFN1) gene can cause familial amyotrophic lateral sclerosis (PMID:22801503)
• No mutations were identified in our cohort suggesting that PFN1 gene mutations are a very rare cause of familial ALS among patients with predominantly European ancestry. (PMID:23062600)
• We detected the p.E117G variant in 1 SALS patient and the novel synonymoufrontotemporal dementia are rare, at least in the Italian population. (PMID:23063648)
• Amyotrophic lateral sclerosis patients with mutations in PFN1 display spinal onset motor neuron disease without overt cognitive involvement. (PMID:23141414)
• PFN1 mutations are not a common cause of frontotemporal lobar degeneration and amyotrophic lateral sclerosis in this cohort of patients from France. (PMID:23182804)
• No mutations were observed in PFN1 in a cohort of Flanders-Belgian frontotemporal lobar degeneration patients. (PMID:23312802)
• Our results demonstrate that increased adhesion, migration and invasiveness of tumor cells depend on the inactivation of the tumor suppressive function of profilin 1 by cathepsin X. (PMID:23326535)
• findings showed Pfn1 overexpression sensitizes cancer cells to apoptosis through the typical intrinsic apoptotic pathway (PMID:23331014)
• Mutations in the profilin 1 gene are not a common cause of amyotrophic lateral sclerosis in a Chinese population. (PMID:23357624)
• The single nucleotide polymorphism (SNP) rs13204 of the PFN1 gene has an important function in the development of amyotrophic lateral sclerosis in Han Chinese. (PMID:23428184)
• Low PFN1 expression is associated with triple-negative breast cancer. (PMID:23430586)
• Wanted to identify estrogen receptor alpha (ERalpha) interacting proteins in Tamoxifen treated MCF7 cells. Using a GST-pull down assay with ERalpha ligand-binding domain and MS-based proteomics approach we identified Profilin1 as a novel ERalpha interacting protein. (PMID:23576398)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pfn1	ENSMUSG00000018293
rattus_norvegicus		ENSRNOG00000068258

Paralogs (2): PFN2 (ENSG00000070087), PFN3 (ENSG00000196570)

Protein

Protein identifiers

Profilin-1 — P07737 (reviewed: P07737)

Alternative names: Epididymis tissue protein Li 184a, Profilin I

All UniProt accessions (3): P07737, I3L3D5, K7EJ44

UniProt curated annotations — full annotation on UniProt →

Function. Binds to actin and affects the structure of the cytoskeleton. At high concentrations, profilin prevents the polymerization of actin, whereas it enhances it at low concentrations. By binding to PIP2, it inhibits the formation of IP3 and DG. Inhibits androgen receptor (AR) and HTT aggregation and binding of G-actin is essential for its inhibition of AR.

Subunit / interactions. Found in a complex with XPO6, Ran, ACTB and PFN1. Interacts with ACTB. Interacts with VASP. Interacts with HTT. Interacts with SH3BGRL. Occurs in many kinds of cells as a complex with monomeric actin in a 1:1 ratio. Interacts with ACTMAP.

Subcellular location. Cytoplasm. Cytoskeleton.

Tissue specificity. Expressed in epididymis (at protein level).

Post-translational modifications. Phosphorylation at Ser-138 reduces its affinity for G-actin and blocks its interaction with HTT, reducing its ability to inhibit androgen receptor (AR) and HTT aggregation.

Disease relevance. Amyotrophic lateral sclerosis 18 (ALS18) [MIM:614808] A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the profilin family.

RefSeq proteins (2): NP_001362920, NP_005013* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005454	Profilin1/2/3_vertebrate	Family
IPR005455	PFN_euk	Family
IPR027310	Profilin_CS	Conserved_site
IPR036140	PFN_sf	Homologous_superfamily
IPR048278	PFN	Family

Pfam: PF00235

UniProt features (32 total): strand 10, modified residue 8, helix 5, sequence variant 4, cross-link 2, initiator methionine 1, chain 1, turn 1

Structure

Experimental structures (PDB)

22 structures.

PDB	Method	Resolution (Å)
2PBD	X-RAY DIFFRACTION	1.5
8BJH	X-RAY DIFFRACTION	1.69
8BJJ	X-RAY DIFFRACTION	1.7
8BJI	X-RAY DIFFRACTION	1.75
2PAV	X-RAY DIFFRACTION	1.8
1FIL	X-RAY DIFFRACTION	2
6NBE	X-RAY DIFFRACTION	2
4X1L	X-RAY DIFFRACTION	2.16
4X1M	X-RAY DIFFRACTION	2.17
1AWI	X-RAY DIFFRACTION	2.2
1CF0	X-RAY DIFFRACTION	2.2
8BR0	X-RAY DIFFRACTION	2.22
4X25	X-RAY DIFFRACTION	2.23
1CJF	X-RAY DIFFRACTION	2.3
1FIK	X-RAY DIFFRACTION	2.3
3CHW	X-RAY DIFFRACTION	2.3
6NBW	X-RAY DIFFRACTION	2.5
6NAS	X-RAY DIFFRACTION	2.9
9AZP	ELECTRON MICROSCOPY	3.79
7P1H	ELECTRON MICROSCOPY	3.9
8RTY	ELECTRON MICROSCOPY	6.25
1PFL	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07737-F1	95.66	0.94

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (10): 54, 54, 2, 28, 57, 85, 105, 108, 129, 138

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-376176	Signaling by ROBO receptors
R-HSA-4086400	PCP/CE pathway
R-HSA-5663220	RHO GTPases Activate Formins

MSigDB gene sets: 457 (showing top): BIOCARTA_RHO_PATHWAY, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, CREL_01, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GNF2_MSN, GCM_MSN, MODULE_151, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, DAZARD_UV_RESPONSE_CLUSTER_G4, MATTIOLI_MGUS_VS_PCL, GOBP_REGULATION_OF_EPITHELIAL_CELL_MIGRATION

GO Biological Process (15): neural tube closure (GO:0001843), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of epithelial cell migration (GO:0010634), actin cytoskeleton organization (GO:0030036), regulation of actin filament polymerization (GO:0030833), positive regulation of actin filament polymerization (GO:0030838), negative regulation of actin filament bundle assembly (GO:0032232), positive regulation of actin filament bundle assembly (GO:0032233), modulation of chemical synaptic transmission (GO:0050804), protein stabilization (GO:0050821), negative regulation of stress fiber assembly (GO:0051497), synapse maturation (GO:0060074), modification of postsynaptic actin cytoskeleton (GO:0098885), positive regulation of ruffle assembly (GO:1900029), regulation of actin filament organization (GO:0110053)

GO Molecular Function (10): adenyl-nucleotide exchange factor activity (GO:0000774), phosphotyrosine residue binding (GO:0001784), RNA binding (GO:0003723), actin binding (GO:0003779), actin monomer binding (GO:0003785), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), small GTPase binding (GO:0031267), cadherin binding (GO:0045296), proline-rich region binding (GO:0070064), protein binding (GO:0005515)

GO Cellular Component (10): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), focal adhesion (GO:0005925), cell cortex (GO:0005938), membrane (GO:0016020), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1
Axon guidance	1
Beta-catenin independent WNT signaling	1
RHO GTPase Effectors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
actin filament polymerization	2
positive regulation of cytoskeleton organization	2
positive regulation of supramolecular fiber organization	2
regulation of actin filament bundle assembly	2
actin filament bundle assembly	2
cytoplasm	2
primary neural tube formation	1
tube closure	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
epithelial cell migration	1
regulation of epithelial cell migration	1
positive regulation of cell migration	1
cytoskeleton organization	1
actin filament-based process	1
regulation of actin polymerization or depolymerization	1
regulation of protein polymerization	1
regulation of actin filament polymerization	1
positive regulation of protein polymerization	1
negative regulation of cytoskeleton organization	1
negative regulation of supramolecular fiber organization	1
positive regulation of cellular component biogenesis	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
regulation of protein stability	1
negative regulation of actin filament bundle assembly	1
stress fiber assembly	1
regulation of stress fiber assembly	1
nervous system development	1
developmental maturation	1
synapse organization	1
modification of postsynaptic structure	1
ruffle assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
regulation of ruffle assembly	1
actin filament organization	1
regulation of actin cytoskeleton organization	1
regulation of supramolecular fiber organization	1
ATP binding	1

Protein interactions and networks

STRING

3148 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PFN1	VASP	P50552	999
PFN1	ACTB	P02570	992
PFN1	WAS	P42768	991
PFN1	XPO6	Q96QU8	990
PFN1	CFL1	P23528	973
PFN1	CFL2	Q9Y281	959
PFN1	GSN	P06396	953
PFN1	TMSB4X	P01253	948
PFN1	APBB1IP	Q7Z5R6	942
PFN1	WASL	O00401	910
PFN1	WIPF1	O43516	896
PFN1	SCIN	Q9Y6U3	874
PFN1	ACTG1	P02571	872
PFN1	FMNL1	O95466	870
PFN1	ACTR2	P61160	864

IntAct

164 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
ACTB	PFN1	psi-mi:“MI:0407”(direct interaction)	0.690
PFN1	ACTB	psi-mi:“MI:0915”(physical association)	0.690
Wasl	PFN1	psi-mi:“MI:0914”(association)	0.640
PFN1	Wasl	psi-mi:“MI:0407”(direct interaction)	0.640
Wasl	PFN1	psi-mi:“MI:0407”(direct interaction)	0.640
PFN1	Wasl	psi-mi:“MI:0915”(physical association)	0.640
WASF1	PFN1	psi-mi:“MI:0915”(physical association)	0.640
ACTA1	PFN1	psi-mi:“MI:0407”(direct interaction)	0.620
act1	PFN1	psi-mi:“MI:0407”(direct interaction)	0.610
act1	PFN1	psi-mi:“MI:0915”(physical association)	0.610
PFN1	VASP	psi-mi:“MI:0915”(physical association)	0.560
ORF putative E6	CASK	psi-mi:“MI:0914”(association)	0.520
E6	CASK	psi-mi:“MI:0914”(association)	0.520
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480

BioGRID (614): PFN1 (Two-hybrid), PFN1 (Affinity Capture-MS), PFN1 (Affinity Capture-MS), PFN1 (Affinity Capture-MS), PFN1 (Affinity Capture-MS), PFN1 (Affinity Capture-MS), CFL1 (Co-fractionation), PFN1 (Co-fractionation), PFN1 (Co-fractionation), PFN1 (Affinity Capture-MS), PFN1 (Affinity Capture-MS), PFN1 (Affinity Capture-MS), PFN1 (Affinity Capture-MS), PFN1 (Affinity Capture-MS), PFN1 (PCA)

ESM2 similar proteins: A4GCR5, A4GCR7, A4GCR8, A4GD50, A4GD54, A4GDQ8, A4GDR9, A4GDT3, A4GE38, A4GE39, A4KA54, A4KA61, A7RT29, A7S6M8, A9UMU8, D3ZVF4, P02584, P06625, P07737, P08240, P35080, P38334, P62962, P62963, Q08CN0, Q09430, Q0P3X8, Q0VGL1, Q29EZ6, Q29NZ8, Q2M2U3, Q2NKT1, Q3MHE8, Q4PM15, Q4R4P8, Q4S4I5, Q54DY3, Q54QW5, Q5IRJ7, Q5R483

Diamond homologs: A0A7H0DND9, O57243, P02584, P07737, P0DSW5, P0DSW6, P62962, P62963, P68695, Q6RZE1, Q76ZN5, Q775N7, Q77DS0, Q77TH1, Q80DT4, Q8JL78, Q8V2L6, Q8V4T7, Q9EPC6, M0RCP6, P35080, P60673, Q09430, Q32PB1, Q4R4P8, Q5R4E2, Q9DAD6, Q9JJV2

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
PPP1CA	up-regulates	PFN1	dephosphorylation
ROCK1	down-regulates	PFN1	phosphorylation
RHOA	“up-regulates activity”	PFN1
PFN1	“up-regulates activity”	CDH4
PFN1	up-regulates	Actin_cytoskeleton_reorganization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 162 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RHO GTPases Activate WASPs and WAVEs	6	16.6×	2e-04
Parasite infection	5	15.1×	8e-04
Leishmania phagocytosis	5	15.1×	8e-04
Dengue Virus Genome Translation and Replication	5	13.8×	1e-03
Oncogenic MAPK signaling	6	12.9×	4e-04
Intrinsic Pathway for Apoptosis	5	12.7×	2e-03
Fcgamma receptor (FCGR) dependent phagocytosis	5	12.1×	2e-03
Signaling by VEGF	6	11.5×	8e-04

GO biological processes:

GO term	Partners	Fold	FDR
autophagosome maturation	5	13.0×	5e-03
mitophagy	5	11.8×	6e-03
ERK1 and ERK2 cascade	5	11.8×	6e-03
positive regulation of miRNA transcription	5	10.8×	9e-03
axonogenesis	7	8.3×	4e-03
mitochondrion organization	7	7.9×	4e-03
negative regulation of gene expression	10	5.1×	4e-03
DNA damage response	11	4.4×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	42
Likely benign	39
Benign	9

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
37034	NM_005022.4(PFN1):c.211T>G (p.Cys71Gly)	Pathogenic
37035	NM_005022.4(PFN1):c.341T>C (p.Met114Thr)	Pathogenic
37036	NM_005022.4(PFN1):c.353G>T (p.Gly118Val)	Pathogenic
1676224	NM_005022.4(PFN1):c.318_319dup (p.Asp107fs)	Likely pathogenic
373953	NM_005022.4(PFN1):c.341T>G (p.Met114Arg)	Likely pathogenic

SpliceAI

414 predictions. Top by Δscore:

Variant	Effect	Δscore
17:4946622:ACT:A	donor_loss	1.0000
17:4946625:CACT:C	donor_loss	1.0000
17:4946626:A:AC	donor_gain	1.0000
17:4946626:A:C	donor_loss	1.0000
17:4946627:C:CA	donor_gain	1.0000
17:4946627:CT:C	donor_gain	1.0000
17:4946627:CTCT:C	donor_gain	1.0000
17:4946627:CTCTT:C	donor_gain	1.0000
17:4946817:CTGG:C	acceptor_gain	1.0000
17:4946819:GG:G	acceptor_gain	1.0000
17:4946820:GC:G	acceptor_loss	1.0000
17:4946821:CTG:C	acceptor_loss	1.0000
17:4945993:TAGCG:T	acceptor_gain	0.9900
17:4945996:CG:C	acceptor_gain	0.9900
17:4945997:GCT:G	acceptor_loss	0.9900
17:4945998:C:CC	acceptor_gain	0.9900
17:4945998:CTG:C	acceptor_loss	0.9900
17:4945999:T:A	acceptor_loss	0.9900
17:4946620:GAAC:G	donor_loss	0.9900
17:4946621:AACT:A	donor_loss	0.9900
17:4946626:ACT:A	donor_gain	0.9900
17:4946627:CTC:C	donor_gain	0.9900
17:4946818:TGG:T	acceptor_gain	0.9900
17:4946821:C:CC	acceptor_gain	0.9900
17:4948210:C:CA	donor_gain	0.9900
17:4948249:AGG:A	donor_gain	0.9900
17:4948261:A:AC	donor_gain	0.9900
17:4948262:C:CC	donor_gain	0.9900
17:4945994:AGCG:A	acceptor_gain	0.9800
17:4945994:AGCGC:A	acceptor_gain	0.9800

AlphaMissense

906 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:4946645:A:T	V103D	1.000
17:4946690:A:G	L88P	1.000
17:4946765:C:T	G63E	1.000
17:4948330:A:T	I22N	1.000
17:4948385:A:G	W4R	1.000
17:4948385:A:T	W4R	1.000
17:4945919:A:G	L135P	0.999
17:4945919:A:T	L135H	0.999
17:4945961:C:T	G121D	0.999
17:4945979:C:T	G115D	0.999
17:4945980:C:G	G115R	0.999
17:4945994:A:G	L110P	0.999
17:4946651:A:T	V101D	0.999
17:4946653:A:C	N100K	0.999
17:4946653:A:T	N100K	0.999
17:4946680:C:A	K91N	0.999
17:4946680:C:G	K91N	0.999
17:4946682:T:C	K91E	0.999
17:4946688:G:T	R89S	0.999
17:4946690:A:T	L88H	0.999
17:4946694:C:G	D87H	0.999
17:4946726:T:A	D76V	0.999
17:4946726:T:G	D76A	0.999
17:4946727:C:G	D76H	0.999
17:4946732:A:C	I74S	0.999
17:4946732:A:T	I74N	0.999
17:4946735:A:T	V73E	0.999
17:4946753:C:T	G67E	0.999
17:4946754:C:A	G67W	0.999
17:4946765:C:A	G63V	0.999

dbSNP variants (sampled 300 via entrez): RS1000012325 (17:4945836 T>C), RS1000193829 (17:4948143 G>A,C,T), RS1000649118 (17:4947960 T>C), RS1001243515 (17:4947457 A>C), RS1001247393 (17:4948788 C>T), RS1001593862 (17:4949021 G>C,T), RS1002162944 (17:4949095 G>A), RS1002198573 (17:4949953 G>A,C), RS1002369755 (17:4945954 C>G), RS1002657497 (17:4949773 C>T), RS1002817546 (17:4947282 G>A,C,T), RS1003371425 (17:4947128 T>C,G), RS1003422075 (17:4946932 T>C), RS1003819219 (17:4946087 G>A), RS1004373326 (17:4947889 G>A,T)

Disease associations

OMIM: gene MIM:176610 | disease phenotypes: MIM:614808

GenCC curated gene-disease

Disease	Classification	Inheritance
amyotrophic lateral sclerosis type 18	Strong	Autosomal dominant
amyotrophic lateral sclerosis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
amyotrophic lateral sclerosis type 18	Definitive	AD

Mondo (3): amyotrophic lateral sclerosis (MONDO:0004976), neurodegenerative disease (MONDO:0005559), amyotrophic lateral sclerosis type 18 (MONDO:0013891)

Orphanet (1): Amyotrophic lateral sclerosis (Orphanet:803)

HPO phenotypes

49 total (30 of 49 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000217	Xerostomia
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000739	Anxiety
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001308	Tongue fasciculations
HP:0001324	Muscle weakness
HP:0001347	Hyperreflexia
HP:0001618	Dysphonia
HP:0001824	Weight loss
HP:0002015	Dysphagia
HP:0002094	Dyspnea
HP:0002145	Frontotemporal dementia
HP:0002180	Neurodegeneration
HP:0002307	Drooling
HP:0002313	Spastic paraparesis
HP:0002360	Sleep disturbance
HP:0002380	Fasciculations
HP:0002463	Language impairment
HP:0002878	Respiratory failure
HP:0003202	Skeletal muscle atrophy
HP:0003324	Generalized muscle weakness
HP:0003376	Steppage gait
HP:0003394	Muscle spasm
HP:0003470	Paralysis
HP:0003484	Upper limb muscle weakness
HP:0003487	Babinski sign

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST90002395_268	Mean platelet volume	5.000000e-12
GCST90013442_27	Keratoconus	2.000000e-14

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D019636	Neurodegenerative Diseases	C10.574

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066975 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.40	Kd	3982	nM	CHEMBL5653589
5.40	ED50	3982	nM	CHEMBL5653589
5.40	Kd	3952	nM	CHEMBL3752910
5.40	ED50	3952	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148984: Binding affinity to human PFN1 incubated for 45 mins by Kinobead based pull down assay	kd	3.9523	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148984: Binding affinity to human PFN1 incubated for 45 mins by Kinobead based pull down assay	kd	3.9820	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	increases expression	3
beauvericin	affects cotreatment, increases expression, decreases expression	2
triphenyl phosphate	affects expression, increases expression	2
bisphenol A	decreases expression, affects expression, affects cotreatment	2
Atrazine	decreases expression, increases expression	2
Benzo(a)pyrene	decreases expression, increases expression, affects reaction	2
Ouabain	affects expression, decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Cadmium Chloride	increases abundance, increases expression	2
Nanotubes, Carbon	affects expression, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
FR900359	decreases phosphorylation	1
pirinixic acid	affects binding, decreases expression, increases activity	1
titanium dioxide	decreases phosphorylation	1
pyrogallol 1,3-dimethyl ether	decreases expression, affects cotreatment, affects localization	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
triphenyltin	decreases expression	1
cupric oxide	decreases expression	1
artenimol	affects binding	1
epigallocatechin gallate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-hydroxy-equilenin	decreases expression	1
tributyltinisothiocyanate	decreases expression	1
CD 437	decreases expression	1
chloropicrin	decreases expression	1
enniatins	affects cotreatment, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652026	Binding	Binding affinity to human PFN1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

10 cell lines: 6 cancer cell line, 4 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C4J6	HAP1 PFN1 (-) 3	Cancer cell line	Male
CVCL_C4J7	HAP1 PFN1 (-) 4	Cancer cell line	Male
CVCL_C4J8	HAP1 PFN1 (-) 5	Cancer cell line	Male
CVCL_E7LQ	KOLF2.1J PFN1 C71G SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E7LR	KOLF2.1J PFN1 C71G SNV/WT	Induced pluripotent stem cell	Male
CVCL_E7LT	KOLF2.1J PFN1 G118V SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E7LU	KOLF2.1J PFN1 G118V SNV/WT	Induced pluripotent stem cell	Male
CVCL_TC97	HAP1 PFN1 (-) 1	Cancer cell line	Male
CVCL_XR54	HAP1 PFN1 (-) 2	Cancer cell line	Male
CVCL_YK62	U2OS tGFP-PFN1	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	PHASE3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04248465	PHASE3	TERMINATED	An Efficacy and Safety Study of Ravulizumab in ALS Participants
NCT04569084	PHASE3	TERMINATED	Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS