HNF1A

Chr 12ARAD

HNF1 homeobox A

Also known as: HNF-1-alpha, HNF-1A, HNF1, HNF1alpha, IDDM20, LFB1, MODY3, TCF-1

NCBI Gene: 6927 ENSG00000135100 UniProt: P20823 OMIM: 142410

This transcription factor regulates tissue-specific gene expression in pancreatic islet cells and liver by binding to specific DNA sequences. Mutations cause maturity-onset diabetes of the young type 3 (MODY3) with autosomal dominant inheritance, as well as autosomal recessive insulin-dependent diabetes mellitus. The gene is highly constrained against loss-of-function variants (pLI 0.96, LOEUF 0.33), reflecting its critical role in pancreatic and hepatic function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/ADLOEUF 0.336 OMIM phenotypes

Clinical Summary— HNF1A

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Gene-Disease Validity (ClinGen)

monogenic diabetes · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

396 unique Pathogenic / Likely Pathogenic· 408 VUS of 1213 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HNF1A

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.33LOEUF

pLI 0.961

Z-score 4.18

OE 0.14 (0.07–0.33)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.14Z-score

OE missense 0.84 (0.76–0.92)

318 obs / 380.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.14 (0.07–0.33)

0≤0.351.4

Missense OE?0.84 (0.76–0.92)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 4 / 27.8Missense obs/exp: 318 / 380.3Syn Z: -1.42

This gene — mechanism propensity

0.3892th %ile

GOF

0.3193th %ile

LOF

0.73top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 59% of P/LP variants are LoF · LOEUF 0.33 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

Literature Evidence

DNThe mutation causes a dominant-negative HNF1A protein variant which blocks HNF1A wild-type-mediated gene expression.The novel Q495X mutation is the likely cause of our patient's diabetes and hepatic adenomatosis.1

LOFHeterozygous loss-of-function mutations in HNF1A cause maturity-onset diabetes of the young (MODY).2

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

References

ClinVar Variant Classifications

1213 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic196

Likely Pathogenic200

VUS408

Likely Benign256

Benign64

Conflicting81

196

Pathogenic

200

Likely Pathogenic

408

VUS

256

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	138	52	6	0	196
Likely Pathogenic	97	96	6	1	200
VUS	10	342	50	6	408
Likely Benign	1	14	70	171	256
Benign	0	19	40	5	64
Conflicting	—				81
Total	246	523	172	183	1,205

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

View in ClinVar →

18 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap HNF1A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →