HNF4A

Chr 20AD

hepatocyte nuclear factor 4 alpha

NCBI Gene: 3172ENSG00000101076UniProt: P41235

Transcriptional regulator which controls the expression of hepatic genes during the transition of endodermal cells to hepatic progenitor cells, facilitating the recruitment of RNA pol II to the promoters of target genes (PubMed:30597922). Activates the transcription of CYP2C38 (By similarity). Represses the CLOCK-BMAL1 transcriptional activity and is essential for circadian rhythm maintenance and period regulation in the liver and colon cells (PubMed:30530698)

Primary Disease Associations & Inheritance

{Diabetes mellitus, noninsulin-dependent}MIM #125853
AD
Fanconi renotubular syndrome 4, with maturity-onset diabetes of the youngMIM #616026
AD
MODY, type IMIM #125850
AD
UniProtType 2 diabetes mellitus
776
ClinVar variants
127
Pathogenic / LP
0.15
pLI score
2
Active trials
Clinical Summary— HNF4A
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.
📋
ClinVar Variants
127 Pathogenic / Likely Pathogenic· 217 VUS of 776 total submissions
💊
Clinical Trials
2 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.
0.51LOEUF
pLI 0.153
Z-score 3.34
OE 0.26 (0.14–0.51)
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.
1.81Z-score
OE missense 0.70 (0.63–0.79)
206 obs / 293.2 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.0.26 (0.14–0.51)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.70 (0.63–0.79)
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.1.09
0≤1.21.6
LoF obs/exp: 6 / 23.4Missense obs/exp: 206 / 293.2Syn Z: -0.79

ClinVar Variant Classifications

776 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic59
Likely Pathogenic68
VUS217
Likely Benign90
Benign16
Conflicting43
59
Pathogenic
68
Likely Pathogenic
217
VUS
90
Likely Benign
16
Benign
43
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
17
12
30
0
59
Likely Pathogenic
17
41
10
0
68
VUS
0
166
48
3
217
Likely Benign
0
3
33
54
90
Benign
0
4
11
1
16
Conflicting
—43
Total3422613258493

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

View in ClinVar →

Protein Context — Lollipop Plot

HNF4A · protein map & ClinVar variants

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

Gene2Phenotype Curations

HNF4A-related atypical Fanconi syndrome with maturity-onset diabetes of the young (MODY)

strong
ADUndeterminedUncertain
Dev. Disorders
G2P ↗

HNF4A-related maturity-onset diabetes of the young (MODY)

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

{Diabetes mellitus, noninsulin-dependent}

MIM #125853

Molecular basis of disorder known

Autosomal dominant

Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young

MIM #616026

Molecular basis of disorder known

Autosomal dominant

MODY, type I

MIM #125850

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Single-cell analyses define a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer.
Becker WR et al.·Nat Genet
2022
Precision diabetes: Lessons learned from maturity-onset diabetes of the young (MODY).
Tosur M et al.·J Diabetes Investig
2022Review
Genotype and phenotype correlations in 417 children with congenital hyperinsulinism.
Snider KE et al.·J Clin Endocrinol Metab
2013
Pathogenic variants in actionable MODY genes are associated with type 2 diabetes.
Bonnefond A et al.·Nat Metab
2020
Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.
Mirshahi UL et al.·Am J Hum Genet
2022Cohort
Congenital Hyperinsulinism: Diagnosis and Treatment Update.
Demirbilek H et al.·J Clin Res Pediatr Endocrinol
2017Review
Monogenic diabetes: a gateway to precision medicine in diabetes.
Zhang H et al.·J Clin Invest
2021Review
Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma.
Montal R et al.·J Hepatol
2020
Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism.
Kapoor RR et al.·Eur J Endocrinol
2013Cohort
Congenital hyperinsulinism: recent updates on molecular mechanisms, diagnosis and management.
Giri D et al.·J Pediatr Endocrinol Metab
2021Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
HNF4A intestinal ablation positively influences the fate of ileal goblet cells during Salmonella typhimurium infection.
Gómez DP et al.·Am J Physiol Gastrointest Liver Physiol
2026
HNF4A-AS1 promotes hepatic steatosis in metabolic dysfunction-associated steatotic liver disease by driving HNF4A degradation.
Yan M et al.·Drug Metab Dispos
2026
Chidamide enhances the sensitivity of gastric cancer to 5-fluorouracil chemotherapy by suppressing the HDAC3/HNF4A/TYMS axis.
Zhang X et al.·Cell Death Dis
2025🔓 Open Access
A Case of Hyperinsulinemic Hypoglycaemia Associated with Atypical Fanconi Renal Tubulopathy Syndrome Caused by an HNF4A Variant.
Garriga-Edo S et al.·Case Rep Nephrol Dial
2026🔓 Open Access
Nandrolone decanoate induces liver damage via TGF-β/Smad3/miR-29 and regulation of FAT/CD36, PTP1B, HNF4A expression in male rats: Rescue effect of N-acetylcysteine.
Mohammadpour-Asl S et al.·J Steroid Biochem Mol Biol
2026
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

External Resources

Links to major genomics databases and tools