HNF4A

Chr 20AD

hepatocyte nuclear factor 4 alpha

Also known as: FRTS4, HNF4, HNF4a7, HNF4a8, HNF4a9, HNF4alpha, MODY, MODY1

NCBI Gene: 3172 ENSG00000101076 UniProt: P41235 OMIM: 600281

The protein encoded by HNF4A is a nuclear transcription factor that controls hepatic gene expression during liver development and maintains circadian rhythm regulation in liver and colon cells. Mutations cause autosomal dominant maturity-onset diabetes of the young (MODY type 1) and Fanconi renotubular syndrome with diabetes, affecting glucose metabolism and kidney tubular function. This gene has low constraint against loss-of-function variants (LOEUF 0.505), and the associated diabetes typically presents in adolescence or young adulthood.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a nuclear transcription factor which binds DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor which regulates the expression of several hepatic genes. This gene may play a role in development of the liver, kidney, and intestines. Mutations in this gene have been associated with monogenic autosomal dominant non-insulin-dependent diabetes mellitus type I. Alternative splicing of this gene results in multiple transcript variants encoding several different isoforms. [provided by RefSeq, Apr 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.513 OMIM phenotypes

Clinical Summary— HNF4A

🧬

Gene-Disease Validity (ClinGen)

monogenic diabetes · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

📋

ClinVar Variants

162 unique Pathogenic / Likely Pathogenic· 274 VUS of 761 total submissions

💊

Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — HNF4A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

1.81Z-score

OE missense 0.70 (0.63–0.79)

206 obs / 293.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.26 (0.14–0.51)

0≤0.351.4

Missense OE?0.70 (0.63–0.79)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 6 / 23.4Missense obs/exp: 206 / 293.2Syn Z: -0.79

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongHNF4A-related atypical Fanconi syndrome with maturity-onset diabetes of the young (MODY)OTHERAD

definitiveHNF4A-related maturity-onset diabetes of the young (MODY)LOFAD

This gene — mechanism propensity

0.6162th %ile

GOF

0.4875th %ile

LOF

0.51top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 47% of P/LP variants are LoF · ClinGen HI: Sufficient evidence for dosage pathogenicity

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

LOFGenotype/phenotype relationships in HNF-4alpha/MODY1: haploinsufficiency is associated with reduced apolipoprotein (AII), apolipoprotein (CIII), lipoprotein(a), and triglyceride levels1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 10905494 ↗

ClinVar Variant Classifications

761 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic72

Likely Pathogenic90

VUS274

Likely Benign165

Benign55

Conflicting101

Pathogenic

Likely Pathogenic

274

VUS

165

Likely Benign

Benign

101

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	41	23	8	0	72
Likely Pathogenic	35	49	6	0	90
VUS	4	207	59	4	274
Likely Benign	0	5	83	77	165
Benign	0	6	47	2	55
Conflicting	—				101
Total	80	290	203	83	757

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap HNF4A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →