FLCN

Chr 17AD

folliculin

Also known as: BHD, DENND8B, FLCL

NCBI Gene: 201163ENSG00000154803UniProt: Q8NFG4

This gene is located within the Smith-Magenis syndrome region on chromosome 17. Mutations in this gene are associated with Birt-Hogg-Dube syndrome, which is characterized by fibrofolliculomas, renal tumors, lung cysts, and pneumothorax. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Birt-Hogg-Dube syndromeMIM #135150
AD
Colorectal cancer, somaticMIM #114500
Pneumothorax, primary spontaneousMIM #173600
AD
Renal carcinoma, chromophobe, somaticMIM #144700
UniProtRenal cell carcinoma
690
ClinVar variants
123
Pathogenic / LP
0.79
pLI score
3
Active trials
Clinical Summary— FLCN
🧬
Gene-Disease Validity (ClinGen)
obsolete Birt-Hogg-Dube syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.79) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
123 Pathogenic / Likely Pathogenic· 316 VUS of 690 total submissions
💊
Clinical Trials
3 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.
0.39LOEUF
pLI 0.789
Z-score 3.94
OE 0.18 (0.10–0.39)
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.
1.13Z-score
OE missense 0.83 (0.75–0.92)
293 obs / 352.7 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.0.18 (0.10–0.39)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.83 (0.75–0.92)
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.1.10
0≤1.21.6
LoF obs/exp: 5 / 27.1Missense obs/exp: 293 / 352.7Syn Z: -0.92

ClinVar Variant Classifications

690 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic101
Likely Pathogenic22
VUS316
Likely Benign222
Benign24
Conflicting5
101
Pathogenic
22
Likely Pathogenic
316
VUS
222
Likely Benign
24
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
63
3
35
0
101
Likely Pathogenic
17
1
2
2
22
VUS
5
281
28
2
316
Likely Benign
0
6
115
101
222
Benign
0
0
5
19
24
Conflicting
—5
Total85291185124690

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

View in ClinVar →

Protein Context — Lollipop Plot

FLCN · protein map & ClinVar variants

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

Gene2Phenotype Curations

FLCN-related Birt-Hogg-Dube syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
SkinCancer
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
FOLLICULIN; FLCN
MIM #607273 · *

Birt-Hogg-Dube syndrome

MIM #135150

Molecular basis of disorder known

Autosomal dominant

Colorectal cancer, somatic

MIM #114500

Molecular basis of disorder known

Pneumothorax, primary spontaneous

MIM #173600

Molecular basis of disorder known

Autosomal dominant

Renal carcinoma, chromophobe, somatic

MIM #144700

Molecular basis of disorder known

📖
GeneReview available — FLCN
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The Metabolic Basis of Kidney Cancer.
Linehan WM et al.·Cancer Discov
2019Review
A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dubé syndrome.
Napolitano G et al.·Nature
2020
The Lysosomal Rag-Ragulator Complex Licenses RIPK1 and Caspase-8-mediated Pyroptosis by Yersinia.
Zheng Z et al.·Science
2021
ERN GENTURIS clinical practice guidelines for the diagnosis, surveillance and management of people with Birt-Hogg-Dubé syndrome.
Geilswijk M et al.·Eur J Hum Genet
2024Review
Birt-Hogg-Dubé syndrome.
Daccord C et al.·Eur Respir Rev
2020
TFEB and TFE3 drive kidney cystogenesis and tumorigenesis.
Di Malta C et al.·EMBO Mol Med
2023
Epidemiology of Renal Cancer: Incidence, Mortality, Survival, Genetic Predisposition, and Risk Factors.
Larcher A et al.·Eur Urol
2025Review
Familial spontaneous pneumothorax.
Chiu HT et al.·Curr Opin Pulm Med
2006Review
Germline- and Somatic-Inactivating FLCN Variants in Parathyroid Cancer and Atypical Parathyroid Tumors.
Jha S et al.·J Clin Endocrinol Metab
2023
Folliculin depletion results in liver cell damage and cholangiocarcinoma through MiT/TFE activation.
Custode BM et al.·Cell Death Differ
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Select updates in the pathology of kidney, testis, and penile cancer for 2026: Including FLCN-mutated (kidney) tumors, paratesticular mesothelial tumors, and TP53/HPV status in penile squamous cell carcinoma.
Tekin B et al.·Hum Pathol
2026
Phenotypic expansion of retinal abnormalities in folliculin (FLCN) variant-related pathology (Birt-Hogg-Dubé syndrome).
August AH et al.·Ophthalmic Genet
2025
Conventional FLCN-mutated tumor: a retrospective study of 5 cases with emphasis on diagnostic challenges.
Wan L et al.·Hum Pathol
2026Cohort
Multiple early onset atypical cutaneous fibrous histiocytomas in multilocus inherited neoplasia allele syndrome involving TP53 and FLCN genes.
Schirwani S et al.·J Med Genet
2025
FLCN-mutated eosinophilic renal tumors: clinicopathologic and molecular analysis of five cases highlighting morphologic heterogeneity.
Zhao M et al.·Virchows Arch
2026Cohort
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Idiopathic Interstitial Pneumopathy/Pneumopathy Interstitial DiffusePaediatric and Adult Patients

RaDiCo PID Cohort (RaDiCo-ILD Cohort in English)

RECRUITING
NCT04238871Institut National de la Santé Et de la Recherche Médicale, FranceStarted 2017-06-21
Lymphoma, Non-HodgkinMultiple MyelomaAdvanced Solid Tumors

Canadian Profiling and Targeted Agent Utilization Trial (CAPTUR)

RECRUITING
NCT03297606Phase PHASE2Canadian Cancer Trials GroupStarted 2018-03-23
OlaparibDasatinibNivolumab plus Ipilimumab
Kidney NeoplasmsKidney CancerPneumothorax

Genetic Analysis of Birt Hogg-Dube Syndrome and Characterization of Predisposition to Kidney Cancer

RECRUITING
NCT00033137National Cancer Institute (NCI)Started 2002-05-13

External Resources

Links to major genomics databases and tools