PAX4

Chr 7ADAR

paired box 4

Also known as: KPD, MODY9

NCBI Gene: 5078ENSG00000106331UniProt: O43316

This gene is a member of the paired box (PAX) family of transcription factors. Members of this gene family typically contain a paired box domain, an octapeptide, and a paired-type homeodomain. These genes play critical roles during fetal development and cancer growth. The paired box 4 gene is involved in pancreatic islet development and mouse studies have demonstrated a role for this gene in differentiation of insulin-producing beta cells. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

{Diabetes mellitus, ketosis-prone, susceptibility to}MIM #612227
ADAR
Diabetes mellitus, type 2MIM #125853
AD
Maturity-onset diabetes of the young, type IXMIM #612225
UniProtType 2 diabetes mellitus
231
ClinVar variants
24
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— PAX4
🧬
Gene-Disease Validity (ClinGen)
monogenic diabetes · ADRefuted

Refuted — evidence has disproved this relationship

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
24 Pathogenic / Likely Pathogenic· 119 VUS of 231 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.89LOEUF
pLI 0.000
Z-score 1.88
OE 0.50 (0.29–0.89)
Tolerant

Typical tolerance to LoF variation

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.
-0.56Z-score
OE missense 1.11 (0.99–1.25)
211 obs / 189.3 exp
Tolerant

Tolerant to missense variation

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.0.50 (0.29–0.89)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.11 (0.99–1.25)
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.1.10
0≤1.21.6
LoF obs/exp: 8 / 16.1Missense obs/exp: 211 / 189.3Syn Z: -0.65

ClinVar Variant Classifications

231 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23
Likely Pathogenic1
VUS119
Likely Benign62
Benign17
Conflicting9
23
Pathogenic
1
Likely Pathogenic
119
VUS
62
Likely Benign
17
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
23
0
23
Likely Pathogenic
0
0
1
0
1
VUS
8
85
24
2
119
Likely Benign
0
11
32
19
62
Benign
1
1
15
0
17
Conflicting
—9
Total9979521231

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

View in ClinVar →

Protein Context — Lollipop Plot

PAX4 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
PAIRED BOX GENE 4; PAX4
MIM #167413 · *

{Diabetes mellitus, ketosis-prone, susceptibility to}

MIM #612227

Molecular basis of disorder known

Autosomal dominantAutosomal recessive

Diabetes mellitus, type 2

MIM #125853

Molecular basis of disorder known

Autosomal dominant

Maturity-onset diabetes of the young, type IX

MIM #612225

Molecular basis of disorder known

📖
GeneReview available — PAX4
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Statistical evidence for high-penetrance MODY-causing genes in a large population-based cohort.
Billings LK et al.·Endocrinol Diabetes Metab
2022Cohort
Pharmacogenomics of glinides.
Chen M et al.·Pharmacogenomics
2015Review
PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development.
Lau HH et al.·Nat Commun
2023
Complete loss of PAX4 causes transient neonatal diabetes in humans.
Russ-Silsby J et al.·Mol Metab
2025
PAX4 R192H and P321H polymorphisms in type 2 diabetes and their functional defects.
Sujjitjoon J et al.·J Hum Genet
2016Functional
C.487C>T mutation in PAX4 gene causes MODY9: A case report and literature review.
Zhang D et al.·Medicine (Baltimore)
2022Review
Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus.
Sommese L et al.·Epigenetics
2017Review
Epigenetic-mediated reprogramming of pancreatic endocrine cells.
Mathiyalagan P et al.·Antioxid Redox Signal
2015Review
Unraveling the genetic basis of MODY: insights from next-generation sequencing.
Eser M et al.·J Appl Genet
2025
Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4.
Ma RC et al.·Diabetologia
2013Meta-analysis
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools