HNF1B

Chr 17AD

HNF1 homeobox B

Also known as: ADTKD3, FJHN, HNF-1-beta, HNF-1B, HNF1beta, HNF2, HPC11, LF-B3

NCBI Gene: 6928ENSG00000275410UniProt: P35680

This gene encodes a member of the homeodomain-containing superfamily of transcription factors. The protein binds to DNA as either a homodimer, or a heterodimer with the related protein hepatocyte nuclear factor 1-alpha. The gene has been shown to function in nephron development, and regulates development of the embryonic pancreas. Mutations in this gene result in renal cysts and diabetes syndrome and noninsulin-dependent diabetes mellitus, and expression of this gene is altered in some types of cancer. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

Primary Disease Associations & Inheritance

{Renal cell carcinoma}MIM #144700
Renal cysts and diabetes syndromeMIM #137920
AD
Type 2 diabetes mellitusMIM #125853
AD
UniProtProstate cancer, hereditary, 11
543
ClinVar variants
188
Pathogenic / LP
1.00
pLI score· haploinsufficient
3
Active trials
Clinical Summary— HNF1B
🧬
Gene-Disease Validity (ClinGen)
renal cysts and diabetes syndrome · ADDefinitive

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
188 Pathogenic / Likely Pathogenic· 178 VUS of 543 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
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.
0.17LOEUF
pLI 1.000
Z-score 4.75
OE 0.04 (0.01–0.17)
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.
1.73Z-score
OE missense 0.72 (0.65–0.81)
225 obs / 311.1 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.0.04 (0.01–0.17)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.65–0.81)
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.1.11
0≤1.21.6
LoF obs/exp: 1 / 28.3Missense obs/exp: 225 / 311.1Syn Z: -1.03

ClinVar Variant Classifications

543 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic135
Likely Pathogenic53
VUS178
Likely Benign125
Benign18
Conflicting34
135
Pathogenic
53
Likely Pathogenic
178
VUS
125
Likely Benign
18
Benign
34
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
27
5
103
0
135
Likely Pathogenic
18
15
20
0
53
VUS
3
150
23
2
178
Likely Benign
0
7
43
75
125
Benign
0
2
15
1
18
Conflicting
—34
Total4817920478543

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

View in ClinVar →

Protein Context — Lollipop Plot

HNF1B · protein map & ClinVar variants

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

Gene2Phenotype Curations

HNF1B-related renal cysts and diabetes syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
HNF1 HOMEOBOX B; HNF1B
MIM #189907 · *

{Renal cell carcinoma}

MIM #144700

Molecular basis of disorder known

Renal cysts and diabetes syndrome

MIM #137920

Molecular basis of disorder known

Autosomal dominant

Type 2 diabetes mellitus

MIM #125853

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — HNF1B
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Autosomal dominant tubulointerstitial kidney disease.
Devuyst O et al.·Nat Rev Dis Primers
2019Review
Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players.
Domingo-Gallego A et al.·Nephrol Dial Transplant
2022
HNF1B-associated renal and extra-renal disease-an expanding clinical spectrum.
Clissold RL et al.·Nat Rev Nephrol
2015Review
Pathogenic variants in actionable MODY genes are associated with type 2 diabetes.
Bonnefond A et al.·Nat Metab
2020
The Landscape of HNF1B Deficiency: A Syndrome Not Yet Fully Explored.
Gambella A et al.·Cells
2023Review
Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications.
Herlin MK·Front Endocrinol (Lausanne)
2024Review
Statistical evidence for high-penetrance MODY-causing genes in a large population-based cohort.
Billings LK et al.·Endocrinol Diabetes Metab
2022Cohort
Exome Sequencing of a Clinical Population for Autosomal Dominant Polycystic Kidney Disease.
Chang AR et al.·JAMA
2022
Single-Cell Transcriptomics Reveals a Conserved Metaplasia Program in Pancreatic Injury.
Ma Z et al.·Gastroenterology
2022
Genomic diagnostics in polycystic kidney disease: an assessment of real-world use of whole-genome sequencing.
Mallawaarachchi AC et al.·Eur J Hum Genet
2021
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
Maturity-onset Diabetes of the YoungMonogenic DiabetesMODY

Identifying Maturity-onset Diabetes of the Young in Emirati Patients

NOT YET RECRUITING
NCT05586594Phase NAUnited Arab Emirates UniversityStarted 2024-03
Genetic testing for 4 MODY genes (GCK, HNF1A, HNF4A, HNF1B)
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING
NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19
Usual Care GroupControlled exercise with telerehabilitation
Adenine Phosphoribosyltransferase DeficiencyAH AmyloidosisAHL Amyloidosis

National Registry of Rare Kidney Diseases

RECRUITING
NCT06065852UK Kidney AssociationStarted 2009-11-06

External Resources

Links to major genomics databases and tools