PDX1

Chr 13ADAR

pancreatic and duodenal homeobox 1

Also known as: GSF, IDX-1, IPF1, IUF1, MODY4, PAGEN1, PDX-1, STF-1

NCBI Gene: 3651 ENSG00000139515 UniProt: P52945 OMIM: 600733

PDX1 encodes a transcriptional activator that regulates insulin, somatostatin, glucokinase, and glucose transporter genes and is essential for pancreatic development and maintaining beta-cell function. Mutations cause pancreatic agenesis with early-onset insulin-dependent diabetes mellitus and maturity-onset diabetes of the young type 4 (MODY4). Inheritance can be either autosomal dominant or autosomal recessive depending on the specific variant and phenotype severity.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAD/ARLOEUF 1.053 OMIM phenotypes

Clinical Summary— PDX1

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Gene-Disease Validity (ClinGen)

monogenic diabetes · ADModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

13 unique Pathogenic / Likely Pathogenic· 129 VUS of 196 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PDX1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

1.05LOEUF

pLI 0.018

Z-score 1.47

OE 0.46 (0.23–1.05)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint

-0.27Z-score

OE missense 1.06 (0.93–1.21)

167 obs / 157.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios

LoF OE0.46 (0.23–1.05)

0≤0.351.4

Missense OE1.06 (0.93–1.21)

0≤0.61.4

Synonymous OE1.41

0≤1.21.6

LoF obs/exp: 4 / 8.7Missense obs/exp: 167 / 157.6Syn Z: -2.81

0.6745th %ile

GOF

0.6053th %ile

LOF

0.49top 25%

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

DNprediction above median · 1 literature citation

LOF1 literature citation · 38% of P/LP variants are LoF

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

DNThis circumstance suggested that the mechanism of diabetes in individuals with this mutation may be not only reduced gene dosage but also a dominant-negative inhibition of transcription of the insulin gene and other beta cell-specific genes regulated by the mutant IPF1.PMID:9649577

LOFHeterozygous loss-of-function mutations cause PDX1-MODY (MODY4).PMID:34988346

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