FOXI1

Chr 5AR

forkhead box I1

Also known as: FKH10, FKHL10, FREAC-6, FREAC6, HFH-3, HFH3

NCBI Gene: 2299ENSG00000168269UniProt: Q12951

This gene belongs to the forkhead family of transcription factors, which is characterized by a distinct forkhead domain. This gene may play an important role in the development of the cochlea and vestibulum, as well as in embryogenesis. The encoded protein has been found to be required for the transcription of four subunits of a proton pump found in the inner ear, the kidney, and the epididymis. Mutations in this gene have been associated with deafness, autosomal recessive 4. [provided by RefSeq, Jan 2017]

Primary Disease Associations & Inheritance

Enlarged vestibular aqueductMIM #600791
AR
249
ClinVar variants
23
Pathogenic / LP
0.77
pLI score
0
Active trials
Clinical Summary— FOXI1
🧬
Gene-Disease Validity (ClinGen)
enlarged vestibular aqueduct syndrome · ARDisputed

Disputed — evidence questions this relationship

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.77) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
23 Pathogenic / Likely Pathogenic· 146 VUS of 249 total submissions

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.
0.51LOEUF
pLI 0.773
Z-score 2.51
OE 0.11 (0.04–0.51)
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.
0.73Z-score
OE missense 0.87 (0.77–0.97)
201 obs / 232.2 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.0.11 (0.04–0.51)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.87 (0.77–0.97)
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.0.99
0≤1.21.6
LoF obs/exp: 1 / 9.2Missense obs/exp: 201 / 232.2Syn Z: 0.07

ClinVar Variant Classifications

249 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18
Likely Pathogenic5
VUS146
Likely Benign51
Benign11
Conflicting18
18
Pathogenic
5
Likely Pathogenic
146
VUS
51
Likely Benign
11
Benign
18
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
17
0
18
Likely Pathogenic
0
4
1
0
5
VUS
1
121
20
4
146
Likely Benign
0
3
10
38
51
Benign
0
0
8
3
11
Conflicting
—18
Total21285645249

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

View in ClinVar →

Protein Context — Lollipop Plot

FOXI1 · 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
FORKHEAD BOX I1; FOXI1
MIM #601093 · *

Enlarged vestibular aqueduct

MIM #600791

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — FOXI1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Molecular Pathophysiology of Acid-Base Disorders.
Wagner CA et al.·Semin Nephrol
2019Review
Reevaluation of Enlarged Vestibular Aqueduct.
Huang S et al.·JAMA Otolaryngol Head Neck Surg
2025
Low-grade oncocytic renal tumor (LOT): mutations in mTOR pathway genes and low expression of FOXI1.
Morini A et al.·Mod Pathol
2022
Analysis of SLC26A4, FOXI1, and KCNJ10 Gene Variants in Patients with Incomplete Partition of the Cochlea and Enlarged Vestibular Aqueduct (EVA) Anomalies.
Klarov LA et al.·Int J Mol Sci
2022Cohort
Abnormal Cellular Populations Shape Thymic Epithelial Tumor Heterogeneity and Anti-Tumor by Blocking Metabolic Interactions in Organoids.
Liu X et al.·Adv Sci (Weinh)
2024
Homozygous Missense Variants in FOXI1 and TMPRSS3 Genes Associated with Non-syndromic Deafness in Moroccan Families.
AitRaise I et al.·Biochem Genet
2024
Acidosis and Deafness in Patients with Recessive Mutations in FOXI1.
Enerbäck S et al.·J Am Soc Nephrol
2018Cohort
Renal Neoplasia in Birt-Hogg-Dubé Syndrome: Integrated Histopathologic, Bulk, and Single-cell Transcriptomic Analysis.
Gupta S et al.·Eur Urol
2025
Transcriptional control of terminal nephron differentiation.
El-Dahr SS et al.·Am J Physiol Renal Physiol
2008Review
Genetics of kidney stone disease-Polygenic meets monogenic.
Halbritter J·Nephrol Ther
2021Review
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