FNIP1

Chr 5AR

folliculin interacting protein 1

Also known as: IMD93

NCBI Gene: 96459ENSG00000217128UniProt: Q8TF40

This gene encodes a protein that binds to the tumor suppressor protein folliculin and to AMP-activated protein kinase (AMPK). The encoded protein participates in the regulation of cellular metabolism and nutrient sensing by modulating the AMPK and target of rapamycin signaling pathways. This gene has a closely related paralog that encodes a protein with similar binding activities. Both related proteins also associate with the molecular chaperone heat shock protein-90 (Hsp90) and negatively regulate its ATPase activity and facilitate its association with folliculin. [provided by RefSeq, Jul 2017]

Primary Disease Associations & Inheritance

Immunodeficiency 93 and hypertrophic cardiomyopathyMIM #619705
AR
400
ClinVar variants
32
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— FNIP1
🧬
Gene-Disease Validity (ClinGen)
FNIP1-associated syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
32 Pathogenic / Likely Pathogenic· 164 VUS of 400 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.25LOEUF
pLI 1.000
Z-score 6.05
OE 0.14 (0.08–0.25)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
2.35Z-score
OE missense 0.73 (0.68–0.79)
449 obs / 612.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.14 (0.08–0.25)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.73 (0.68–0.79)
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.0.93
0≤1.21.6
LoF obs/exp: 8 / 57.6Missense obs/exp: 449 / 612.9Syn Z: 0.79

ClinVar Variant Classifications

400 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29
Likely Pathogenic3
VUS164
Likely Benign184
Benign20
29
Pathogenic
3
Likely Pathogenic
164
VUS
184
Likely Benign
20
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
0
22
0
29
Likely Pathogenic
2
1
0
0
3
VUS
2
156
5
1
164
Likely Benign
0
8
64
112
184
Benign
0
5
9
6
20
Total11170100119400

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

View in ClinVar →

Protein Context — Lollipop Plot

FNIP1 · 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

Immunodeficiency 93 and hypertrophic cardiomyopathy

MIM #619705

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — FNIP1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Muscle-bone cross-talk through the FNIP1-TFEB-IGF2 axis is associated with bone metabolism in human and mouse.
Mao Y et al.·Sci Transl Med
2024Functional
Antagonistic roles for MITF and TFE3 in melanoma plasticity.
Chang J et al.·Cell Rep
2025
Clinical and Immunologic Features of a Patient With Homozygous FNIP1 Variant.
Ulaş S et al.·J Pediatr Hematol Oncol
2024Case report
Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome.
Schmidt LS et al.·Nat Rev Urol
2015Review
A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy.
Spivak I et al.·Immunogenetics
2024Case report
Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity.
Siggs OM et al.·Proc Natl Acad Sci U S A
2016
Familial multiple discoid fibromas is linked to a locus on chromosome 5 including the FNIP1 gene.
van de Beek I et al.·J Hum Genet
2023
Birt-Hogg-Dube syndrome: clinicopathological features of the lung.
Furuya M et al.·J Clin Pathol
2013Review
Birt-Hogg-Dubé syndrome: Clinical and molecular aspects of recently identified kidney cancer syndrome.
Hasumi H et al.·Int J Urol
2016Review
Molecular chaperones: Guardians of tumor suppressor stability and function.
Heritz JA et al.·Oncotarget
2024Review
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools