PFN1

Chr 17

profilin 1

Also known as: ALS18

NCBI Gene: 5216ENSG00000108518UniProt: P07737

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. [provided by RefSeq, Jul 2012]

Primary Disease Associations & Inheritance

Amyotrophic lateral sclerosis 18MIM #614808
145
ClinVar variants
29
Pathogenic / LP
0.73
pLI score
9
Active trials
Clinical Summary— PFN1
🧬
Gene-Disease Validity (ClinGen)
amyotrophic lateral sclerosis type 18 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.73) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
29 Pathogenic / Likely Pathogenic· 54 VUS of 145 total submissions
💊
Clinical Trials
9 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.69LOEUF
pLI 0.733
Z-score 1.93
OE 0.00 (0.00–0.69)
Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.95Z-score
OE missense 0.41 (0.31–0.54)
35 obs / 85.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.69)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.41 (0.31–0.54)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.30
0≤1.21.6
LoF obs/exp: 0 / 4.4Missense obs/exp: 35 / 85.9Syn Z: -1.40

ClinVar Variant Classifications

145 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25
Likely Pathogenic4
VUS54
Likely Benign46
Benign14
Conflicting2
25
Pathogenic
4
Likely Pathogenic
54
VUS
46
Likely Benign
14
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
3
22
0
25
Likely Pathogenic
1
1
2
0
4
VUS
1
35
18
0
54
Likely Benign
1
1
25
19
46
Benign
0
0
11
3
14
Conflicting
—2
Total3407822145

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PFN1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
PROFILIN 1; PFN1
MIM #176610 · *

Amyotrophic lateral sclerosis 18

MIM #614808

Molecular basis of disorder known

📖
GeneReview available — PFN1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
m(6)A Modification of Profilin-1 in Vascular Smooth Muscle Cells Drives Phenotype Switching and Neointimal Hyperplasia via Activation of the p-ANXA2/STAT3 Pathway.
Gao XF et al.·Arterioscler Thromb Vasc Biol
2024
Comparison between PFN1 and SOD1 mutations in amyotrophic lateral sclerosis.
Corcia P et al.·Eur J Neurol
2023Review
Oedematic-atrophic astrocytes in hepatic encephalopathy.
Popek M et al.·Acta Neuropathol Commun
2025
Visualizing molecules of functional human profilin.
Pimm ML et al.·Elife
2022Functional
Profilin1 is required for prevention of mitotic catastrophe in murine and human glomerular diseases.
Tian X et al.·J Clin Invest
2023
Identification and validation of a novel defined stress granule-related gene signature for predicting the prognosis of ovarian cancer via bioinformatics analysis.
Chen X et al.·Medicine (Baltimore)
2024
The actin binding protein profilin 1 localizes inside mitochondria and is critical for their function.
Read TA et al.·EMBO Rep
2024
Lactylation modulation identifies key biomarkers and therapeutic targets in KMT2A-rearranged AML.
Liu D et al.·Sci Rep
2025
Integrated single-cell and bulk RNA sequencing reveals immune-related SPP1+ macrophages as a potential strategy for predicting the prognosis and treatment of liver fibrosis and hepatocellular carcinoma.
Li B et al.·Front Immunol
2024
The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis.
Teyssou E et al.·Int J Mol Sci
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
F-Box and Leucine-Rich Repeat Protein 4 (FBXL4) Maintains Sarcomere Integrity and Cardiac Function by Enhancing K48-Linked Ubiquitinated Degradation of Profilin-1 (PFN1).
Li X et al.·Adv Sci (Weinh)
2026
A Missense Mutation in Close Proximity of ALS-linked PFN1 Mutations Causes Only Early-onset Paget Disease of Bone.
Weng R et al.·J Clin Endocrinol Metab
2025🔓 Open Access
MAIT Cells with High PFN1 Expression Mediate Immune Activation and Metabolic Reprogramming in Psoriasis.
Wu MN et al.·Clin Cosmet Investig Dermatol
2025🔓 Open Access
Metal Ion Nanodepots Orchestrate Neuronal Axon and Dendrite Growth via the Actin-PFN1 Pathway.
Yang Y et al.·ACS Appl Mater Interfaces
2025
Viral-mediated knockdown of Atxn2 attenuates TDP-43 pathology and muscle dysfunction in the PFN1C71G ALS mouse model.
Hawley ZCE et al.·Acta Neuropathol Commun
2025🔓 Open AccessFunctional
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
ALS

Amyotrophic Lateral Sclerosis (ALS) Families Project

RECRUITING
NCT03865420Columbia UniversityStarted 2018-09-11
Malnutrition PregnancyMalnutrition in ChildrenMalnutrition (Calorie)

Early Life Malnutrition, Environmental Enteric Dysfunction and Microbiome Trajectories

RECRUITING
NCT07195006University of ZimbabweStarted 2025-01-27
Malnutrition in pregnancy as exposurePoor WASH living conditions as exposure
Diabetes MellitusPancreas TransplantationAllograft Rejection

The Norwegian Pancreas Transplantation (PTx) Study

ENROLLING BY INVITATION
NCT01957696Oslo University HospitalStarted 2013-09
EndometriosisAdenomyosis

Pain in Endometriosis And the Relation to Lifestyle

RECRUITING
NCT06332560Phase NARadboud University Medical CenterStarted 2024-10-04
Anti-inflammatory diet (DI)Cognitive behavioral therapy (CBT)
Transplantation InfectionKidney Diseases

Molecular Biological and Moleculargenetic Monitoring of Therapy After Kidney Transplantation

RECRUITING
NCT01515605Odense University HospitalStarted 2011-01-01
Early Breast CancerTriple Negative Breast Cancer

Trial for Treatment of High Risk BC With Two Sequences of Neoadjuvant Chemotherapy With Pembrolizumab

NOT YET RECRUITING
NCT06371807Phase PHASE2Fundacao ChampalimaudStarted 2024-07
Pembrolizumab injection
Bladder Cancer

Antitumor T Cell Responses in Patients With Bladder Cancer

NOT YET RECRUITING
NCT06334406Centre Hospitalier Universitaire de BesanconStarted 2024-04-02
Biological samples
Post-Acute COVID-19 Syndrome

A Study of Apabetalone in Subjects With Long -COVID

RECRUITING
NCT06590324Phase PHASE2, PHASE3Resverlogix CorpStarted 2025-04-15
Apabetalone
Myelodysplastic Syndrome

Study of an Innovative Therapy Using CAR-T Cells Targeting IL-1RAP in Patients With High-Risk Myelodysplastic Syndromes (MDS

NOT YET RECRUITING
NCT07455500Phase NAUniversity Hospital, GrenobleStarted 2026-05
Bone marrow and blood sampling

External Resources

Links to major genomics databases and tools