GRN

Chr 17ADAR

granulin precursor

NCBI Gene: 2896ENSG00000030582UniProt: P28799

Secreted protein that acts as a key regulator of lysosomal function and as a growth factor involved in inflammation, wound healing and cell proliferation (PubMed:12526812, PubMed:18378771, PubMed:28073925, PubMed:28453791, PubMed:28541286). Regulates protein trafficking to lysosomes, and also the activity of lysosomal enzymes (PubMed:28453791, PubMed:28541286). Also facilitates the acidification of lysosomes, causing degradation of mature CTSD by CTSB (PubMed:28073925). In addition, functions as a wound-related growth factor that acts directly on dermal fibroblasts and endothelial cells to promote division, migration and the formation of capillary-like tubule structures (By similarity). Also promotes epithelial cell proliferation by blocking TNF-mediated neutrophil activation preventing release of oxidants and proteases (PubMed:12526812). Moreover, modulates inflammation in neurons by preserving neurons survival, axonal outgrowth and neuronal integrity (PubMed:18378771)

Primary Disease Associations & Inheritance

Aphasia, primary progressiveMIM #607485
ADAR
Ceroid lipofuscinosis, neuronal, 11MIM #614706
AR
Frontotemporal dementia 2MIM #607485
ADAR
581
ClinVar variants
70
Pathogenic / LP
0.07
pLI score
8
Active trials
Clinical Summary— GRN
🧬
Gene-Disease Validity (ClinGen)
neuronal ceroid lipofuscinosis · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.
📋
ClinVar Variants
70 Pathogenic / Likely Pathogenic· 284 VUS of 581 total submissions
💊
Clinical Trials
8 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.
0.48LOEUF
pLI 0.070
Z-score 3.71
OE 0.27 (0.16–0.48)
Moderately constrained

More LoF-intolerant than ~75% of genes

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.
0.28Z-score
OE missense 0.96 (0.88–1.05)
341 obs / 355.6 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.0.27 (0.16–0.48)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.96 (0.88–1.05)
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.1.13
0≤1.21.6
LoF obs/exp: 8 / 29.9Missense obs/exp: 341 / 355.6Syn Z: -1.25

ClinVar Variant Classifications

581 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic55
Likely Pathogenic15
VUS284
Likely Benign206
Benign8
Conflicting13
55
Pathogenic
15
Likely Pathogenic
284
VUS
206
Likely Benign
8
Benign
13
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
31
3
21
0
55
Likely Pathogenic
13
1
1
0
15
VUS
3
251
23
7
284
Likely Benign
0
3
80
123
206
Benign
0
0
7
1
8
Conflicting
—13
Total47258132131581

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

View in ClinVar →

Protein Context — Lollipop Plot

GRN · protein map & ClinVar variants

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

Gene2Phenotype Curations

GRN-related ceroid lipofuscinosis, neuronal

strong
ARLoss Of FunctionAbsent Gene Product
Eye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
GRANULIN PRECURSOR; GRN
MIM #138945 · *

Aphasia, primary progressive

MIM #607485

Molecular basis of disorder known

Autosomal dominantAutosomal recessive

Ceroid lipofuscinosis, neuronal, 11

MIM #614706

Molecular basis of disorder known

Autosomal recessive

Frontotemporal dementia 2

MIM #607485

Molecular basis of disorder known

Autosomal dominantAutosomal recessive
📖
GeneReview available — GRN
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Frontotemporal Dementia.
Clark DG·Continuum (Minneap Minn)
2024Review
An update on genetic frontotemporal dementia.
Greaves CV et al.·J Neurol
2019Review
Identification of potential ferroptosis-associated biomarkers in rheumatoid arthritis.
He X et al.·Front Immunol
2023
Robust gene expression programs underlie recurrent cell states and phenotype switching in melanoma.
Wouters J et al.·Nat Cell Biol
2020
Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration.
Saloner R et al.·Nat Aging
2025
Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results.
Sevigny J et al.·Nat Med
2024Clinical trial
Modifiers of GRN-Associated Frontotemporal Lobar Degeneration.
Wauters E et al.·Trends Mol Med
2017Review
Whole exome sequencing analyses identified novel genes for Alzheimer's disease and related dementia.
Zhang YR et al.·Alzheimers Dement
2024
Frontotemporal dementia.
Perry DC et al.·Semin Neurol
2013Review
Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study.
Moore KM et al.·Lancet Neurol
2020Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Neuronal Ceroid LipofuscinosisBatten DiseaseCLN1 Disease

Natural History and Longitudinal Clinical Assessments in NCL / Batten Disease, the International DEM-CHILD Database

RECRUITING
NCT04613089Universitätsklinikum Hamburg-EppendorfStarted 2020-04-08
Natural History
Frontotemporal Dementia

Phase 1/2 Clinical Trial of LY3884963 in Patients With Frontotemporal Dementia With Progranulin Mutations (FTD-GRN)

ACTIVE NOT RECRUITING
NCT04408625Phase PHASE1, PHASE2Prevail TherapeuticsStarted 2020-11-09
LY3884963MethylprednisoloneOptional Sirolimus
Frontotemporal Lobar Degeneration (FTLD)Progressive Supranuclear Palsy (PSP)Corticobasal Degeneration (CBD)

ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD)

RECRUITING
NCT04363684Mayo ClinicStarted 2020-03-01
Amyotrophic Lateral Sclerosis

Development of Targeted RNA-Seq for Amyotrophic Lateral Sclerosis Diagnosis

RECRUITING
NCT06083584Centre Hospitalier Universitaire de NīmesStarted 2023-11-22
RNA sequencing
Frontotemporal DementiaFTDFTD-GRN

A Study of PBFT02 in Participants With FTD and Mutations in the Granulin Precursor (GRN) or C9ORF72 Genes

RECRUITING
NCT04747431Phase PHASE1, PHASE2Passage Bio, Inc.Started 2021-09-14
PBFT02
Spinal StenosisLigamentum Flavum Hypertrophy

Cytokines, Neuroplasticity Modulators, and Biomarkers in Spinal Canal Stenosis and Endoscopic Decompression

NOT YET RECRUITING
NCT07232836Phase NAPoznan University of Physical EducationStarted 2025-11-17
Endoscopic Spinal Canal Decompression
Frontotemporal DementiaFTDFTD-GRN

A Study to Evaluate the Safety and Effect of AVB-101, a Gene Therapy Product, in Subjects With a Genetic Sub-type of Frontotemporal Dementia (FTD-GRN)

RECRUITING
NCT06064890Phase PHASE1, PHASE2AviadoBio LtdStarted 2023-08-30
Intrathalamic AAV.PGRN administrationIntrathalamic AVB-101
Frontotemporal Lobar DegenerationAlzheimer DiseaseCognitively Normal

PET Imaging Tau Accumulation in FTLD and Atypical Alzheimer's Using [18F]-PI-2620

RECRUITING
NCT05456503Phase PHASE3University of PennsylvaniaStarted 2022-09-19
[18F]-PI-2620

External Resources

Links to major genomics databases and tools