Pancreatic agenesis 1

Summary

Pancreatic agenesis 1 (MONDO:0024547) is a disease caused by PDX1 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Causal gene: PDX1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 58
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pancreatic agenesis 1
Mondo ID	MONDO:0024547
OMIM	260370
DOID	DOID:0061003
UMLS	C3891828
MedGen	856095
GARD	0015220
Is cancer (heuristic)	no

Also known as: PAGEN1 · pancreatic agenesis 1 · pancreatic agenesis caused by mutation in PDX1 · PDX1 pancreatic agenesis

Data availability: 58 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › pancreatic agenesis › pancreatic agenesis 1

Related subtypes (3): pancreas, dorsal, agenesis of, pancreatic agenesis 2, pancreatic agenesis 3

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

58 retrieved; paginated sample, class counts are floors:

44 uncertain significance, 6 conflicting classifications of pathogenicity, 2 benign/likely benign, 2 likely pathogenic, 2 pathogenic, 1 likely benign, 1 pathogenic; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
30124	NM_000209.4(PDX1):c.533A>G (p.Glu178Gly)	PDX1	Pathogenic	criteria provided, single submitter
8864	NM_000209.4(PDX1):c.492G>T (p.Glu164Asp)	PDX1	Pathogenic; risk factor	no assertion criteria provided
8865	NM_000209.4(PDX1):c.532G>A (p.Glu178Lys)	PDX1	Pathogenic	criteria provided, single submitter
1755049	NM_000209.4(PDX1):c.671_672dup (p.Gln225fs)	PDX1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
436282	NM_000209.4(PDX1):c.502A>C (p.Asn168His)	PDX1	Likely pathogenic	criteria provided, single submitter
1043044	NM_000209.4(PDX1):c.211C>A (p.Pro71Thr)	PDX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1256412	NM_000209.4(PDX1):c.97C>G (p.Pro33Ala)	PDX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
21124	NM_000209.4(PDX1):c.188del (p.Pro63fs)	PDX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
36413	NM_000209.4(PDX1):c.773A>G (p.Glu258Gly)	PDX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
449080	NM_000209.4(PDX1):c.820G>T (p.Val274Phe)	PDX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
668654	NM_000209.4(PDX1):c.848G>A (p.Arg283Gln)	PDX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1200171	NM_000209.4(PDX1):c.463C>A (p.Arg155Ser)	PDX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1336622	NM_000209.4(PDX1):c.101C>T (p.Ala34Val)	PDX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1408111	NM_000209.4(PDX1):c.296C>A (p.Pro99His)	PDX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1409937	NM_000209.4(PDX1):c.841G>C (p.Glu281Gln)	PDX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1415209	NM_000209.4(PDX1):c.98C>A (p.Pro33His)	PDX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1708924	NM_000209.4(PDX1):c.664G>A (p.Glu222Lys)	PDX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1749138	NM_000209.4(PDX1):c.569T>C (p.Ile190Thr)	PDX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1898245	NM_000209.4(PDX1):c.97C>T (p.Pro33Ser)	PDX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2171868	NM_000209.4(PDX1):c.92G>A (p.Ser31Asn)	PDX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2442632	NM_000209.4(PDX1):c.284C>A (p.Pro95Gln)	PDX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3383115	NM_000209.4(PDX1):c.433G>A (p.Glu145Lys)	PDX1	Uncertain significance	criteria provided, single submitter
3575830	NM_000209.4(PDX1):c.84C>G (p.Phe28Leu)	PDX1	Uncertain significance	criteria provided, single submitter
3575832	NM_000209.4(PDX1):c.124C>A (p.Pro42Thr)	PDX1	Uncertain significance	criteria provided, single submitter
3575833	NM_000209.4(PDX1):c.146C>G (p.Pro49Arg)	PDX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3575834	NM_000209.4(PDX1):c.184C>A (p.Pro62Thr)	PDX1	Uncertain significance	criteria provided, single submitter
3575835	NM_000209.4(PDX1):c.190G>A (p.Asp64Asn)	PDX1	Uncertain significance	criteria provided, single submitter
3575836	NM_000209.4(PDX1):c.272C>T (p.Ala91Val)	PDX1	Uncertain significance	criteria provided, single submitter
3575837	NM_000209.4(PDX1):c.280C>T (p.His94Tyr)	PDX1	Uncertain significance	criteria provided, single submitter
3575838	NM_000209.4(PDX1):c.286C>G (p.Pro96Ala)	PDX1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 30 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PDHX	Strong	Autosomal recessive	pancreatic agenesis 1	18
PDX1	Strong	Autosomal recessive	pancreatic agenesis 1	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PDHX	Orphanet:255182	Pyruvate dehydrogenase E3-binding protein deficiency
PDX1	Orphanet:2805	Partial pancreatic agenesis
PDX1	Orphanet:552	MODY
PDX1	Orphanet:99885	Isolated permanent neonatal diabetes mellitus

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PDHX	HGNC:21350	ENSG00000110435	O00330	Pyruvate dehydrogenase protein X component, mitochondrial	gencc,clinvar
PDX1	HGNC:6107	ENSG00000139515	P52945	Pancreas/duodenum homeobox protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PDHX	Pyruvate dehydrogenase protein X component, mitochondrial	Required for anchoring dihydrolipoamide dehydrogenase (E3) to the dihydrolipoamide transacetylase (E2) core of the pyruvate dehydrogenase complexes of eukaryotes.
PDX1	Pancreas/duodenum homeobox protein 1	Activates insulin, somatostatin, glucokinase, islet amyloid polypeptide and glucose transporter type 2 gene transcription.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PDHX	Enzyme (other)	yes	1.2.1.104	Biotin_lipoyl, 2-oxoacid_DH_actylTfrase, 2-oxoA_DH_lipoyl-BS
PDX1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
heart right ventricle	1
skeletal muscle tissue of biceps brachii	1
body of pancreas	1
islet of Langerhans	1
pancreas	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PDHX	296	ubiquitous	marker	biceps brachii, heart right ventricle, skeletal muscle tissue of biceps brachii
PDX1	30	tissue_specific	marker	islet of Langerhans, pancreas, body of pancreas

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PDHX	3,542
PDX1	1,203

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PDHX	O00330	5
PDX1	P52945	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
PDH complex synthesizes acetyl-CoA from PYR	1	815.7×	0.006	PDHX
Regulation of gene expression in early pancreatic precursor cells	1	713.8×	0.006	PDX1
Regulation of pyruvate dehydrogenase (PDH) complex	1	356.9×	0.006	PDHX
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	300.5×	0.006	PDX1
Regulation of gene expression in beta cells	1	259.6×	0.006	PDX1
Signaling by Retinoic Acid	1	203.9×	0.007	PDHX
Developmental Lineage of Pancreatic Acinar Cells	1	150.3×	0.008	PDX1
Developmental Lineage of Pancreatic Ductal Cells	1	114.2×	0.009	PDX1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cellular response to acadesine	1	8426.0×	0.003	PDX1
response to chlorate	1	4213.0×	0.003	PDX1
response to vitamin	1	4213.0×	0.003	PDX1
response to L-leucine	1	2808.7×	0.003	PDX1
type B pancreatic cell apoptotic process	1	2808.7×	0.003	PDX1
positive regulation of type B pancreatic cell proliferation	1	1685.2×	0.003	PDX1
response to iron(II) ion	1	1203.7×	0.003	PDX1
type B pancreatic cell differentiation	1	1053.2×	0.003	PDX1
pyruvate decarboxylation to acetyl-CoA	1	1053.2×	0.003	PDHX
glucose mediated signaling pathway	1	1053.2×	0.003	PDX1
transdifferentiation	1	1053.2×	0.003	PDX1
negative regulation of type B pancreatic cell apoptotic process	1	1053.2×	0.003	PDX1
exocrine pancreas development	1	842.6×	0.003	PDX1
morphogenesis of embryonic epithelium	1	766.0×	0.003	PDX1
response to alkaloid	1	766.0×	0.003	PDX1
response to fatty acid	1	526.6×	0.005	PDX1
type B pancreatic cell proliferation	1	443.5×	0.005	PDX1
negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1	421.3×	0.005	PDX1
animal organ regeneration	1	300.9×	0.007	PDX1
digestive tract development	1	263.3×	0.007	PDX1
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1	240.7×	0.008	PDX1
insulin secretion	1	216.1×	0.008	PDX1
response to nicotine	1	210.7×	0.008	PDX1
response to cytokine	1	187.2×	0.008	PDX1
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	187.2×	0.008	PDX1
generation of precursor metabolites and energy	1	172.0×	0.009	PDX1
response to glucocorticoid	1	162.0×	0.009	PDX1
stem cell differentiation	1	150.5×	0.009	PDX1
negative regulation of epithelial cell proliferation	1	145.3×	0.009	PDX1
glucose metabolic process	1	127.7×	0.010	PDX1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PDHX	0	0
PDX1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PDHX	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PDHX	1.2.1.104	pyruvate dehydrogenase system

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PDHX
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PDX1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PDHX	1	—
PDX1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns