Polymerase proofreading-related adenomatous polyposis

Summary

Polymerase proofreading-related adenomatous polyposis (MONDO:0018653) is a disease with 3 cohort genes and 1 clinical trial.

At a glance

• Cohort genes: 3
• ClinVar variants: 201
• Phenotypes (HPO): 7
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

7 HPO clinical features (Orphanet curated; top 7 by frequency):

HPO ID	Term	Frequency
HP:0005227	Adenomatous colonic polyposis	Frequent (30-79%)
HP:0012114	Endometrial carcinoma	Frequent (30-79%)
HP:0200063	Colorectal polyposis	Frequent (30-79%)
HP:0003002	Breast carcinoma	Occasional (5-29%)
HP:0030692	Brain neoplasm	Occasional (5-29%)
HP:0040276	Adenocarcinoma of the colon	Occasional (5-29%)
HP:0100743	Neoplasm of the rectum	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Polymerase proofreading-related adenomatous polyposis
Mondo ID	MONDO:0018653
Orphanet	447877
NCIT	C162484
UMLS	C5202613
MedGen	1687472
GARD	0017772
Is cancer (heuristic)	no

Also known as: Polymerase proofreading-related adenomatous polyposis · PPAP

Data availability: 201 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › intestinal polyposis syndrome › classic or attenuated familial adenomatous polyposis › Polymerase proofreading-related adenomatous polyposis

Related subtypes (7): familial adenomatous polyposis 2, familial adenomatous polyposis 3, attenuated familial adenomatous polyposis, AXIN2-related attenuated familial adenomatous polyposis, classic familial adenomatous polyposis, familial adenomatous polyposis 1, familial adenomatous polyposis 4

Subtypes (2): POLE-related polyposis and colorectal cancer syndrome, POLD1-related polyposis and colorectal cancer syndrome

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

201 retrieved; paginated sample, class counts are floors:

59 conflicting classifications of pathogenicity, 57 uncertain significance, 41 benign/likely benign, 39 likely benign, 4 benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
40046	NM_006231.4(POLE):c.1270C>G (p.Leu424Val)	POLE	Pathogenic	criteria provided, multiple submitters, no conflicts
2752061	NM_006231.4(POLE):c.62+1G>A	LOC130009266	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
512346	NM_006231.4(POLE):c.-9A>G	LOC130009266	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
645544	NM_006231.4(POLE):c.43G>C (p.Ala15Pro)	LOC130009266	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
220886	NM_002691.4(POLD1):c.1795G>A (p.Ala599Thr)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
221172	NM_002691.4(POLD1):c.2301G>A (p.Ser767=)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239278	NM_002691.4(POLD1):c.2250+4G>A	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239329	NM_002691.4(POLD1):c.3054G>A (p.Val1018=)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239338	NM_002691.4(POLD1):c.3257G>A (p.Arg1086Gln)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239340	NM_002691.4(POLD1):c.3290G>A (p.Arg1097Gln)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
245862	NM_002691.4(POLD1):c.80A>T (p.Asp27Val)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
372064	NM_002691.4(POLD1):c.3121-14G>A	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
408055	NM_002691.4(POLD1):c.1243-11CTC[2]	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
408069	NM_002691.4(POLD1):c.3016G>A (p.Ala1006Thr)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
572544	NM_002691.4(POLD1):c.3292C>T (p.Arg1098Cys)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1112863	NM_006231.4(POLE):c.5274C>T (p.Phe1758=)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1137945	NM_006231.4(POLE):c.4862T>G (p.Val1621Gly)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
220739	NM_006231.4(POLE):c.6004+5G>T	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
220924	NM_006231.4(POLE):c.3582+5C>T	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
221094	NM_006231.4(POLE):c.2706+5G>A	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240370	NM_006231.4(POLE):c.1007A>G (p.Asn336Ser)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240374	NM_006231.4(POLE):c.1064A>G (p.Lys355Arg)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240396	NM_006231.4(POLE):c.154C>T (p.Arg52Trp)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240439	NM_006231.4(POLE):c.2645A>G (p.Asn882Ser)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240452	NM_006231.4(POLE):c.296C>T (p.Pro99Leu)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240475	NM_006231.4(POLE):c.3718G>A (p.Glu1240Lys)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240482	NM_006231.4(POLE):c.3862G>A (p.Ala1288Thr)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240500	NM_006231.4(POLE):c.4057A>G (p.Ser1353Gly)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240565	NM_006231.4(POLE):c.553G>A (p.Asp185Asn)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240582	NM_006231.4(POLE):c.6050G>A (p.Arg2017His)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 28 · Orphanet: 7 · 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
POLD1	Definitive	Autosomal dominant	POLD1-related polyposis and colorectal cancer syndrome	15
POLE	Definitive	Autosomal dominant	POLE-related polyposis and colorectal cancer syndrome	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLD1	Orphanet:363649	Mandibular hypoplasia-deafness-progeroid features-lipodystrophy syndrome
POLD1	Orphanet:440437	Familial colorectal cancer Type X
POLD1	Orphanet:447877	Polymerase proofreading-related polyposis
POLE	Orphanet:352712	Facial dysmorphism-immunodeficiency-livedo-short stature syndrome
POLE	Orphanet:440437	Familial colorectal cancer Type X
POLE	Orphanet:447877	Polymerase proofreading-related polyposis
POLE	Orphanet:85173	IMAGe syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
POLD1	HGNC:9175	ENSG00000062822	P28340	DNA polymerase delta catalytic subunit	gencc,clinvar
POLE	HGNC:9177	ENSG00000177084	Q07864	DNA polymerase epsilon catalytic subunit A	gencc,clinvar
EXOC4	HGNC:30389	ENSG00000131558	Q96A65	Exocyst complex component 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLD1	DNA polymerase delta catalytic subunit	As the catalytic component of the trimeric (Pol-delta3 complex) and tetrameric DNA polymerase delta complexes (Pol-delta4 complex), plays a crucial role in high fidelity genome replication, including in lagging strand synthesis, and repair.
POLE	DNA polymerase epsilon catalytic subunit A	Catalytic component of the DNA polymerase epsilon complex.
EXOC4	Exocyst complex component 4	Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.0

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
Transcription factor	2	5.5×	0.081
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POLD1	Transcription factor	no	2.7.7.7	DNA-dir_DNA_pol_B_exonuc, DNA-dir_DNA_pol_B_multi_dom, DNA-dir_DNA_pol_B
POLE	Transcription factor	no	2.7.7.7	DNA-dir_DNA_pol_B_exonuc, DNA-dir_DNA_pol_B, RNaseH-like_sf
EXOC4	Other/Unknown	no		Sec8_exocyst_N, Sec8/EXOC4, Sec8_M

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of transverse colon	1
primordial germ cell in gonad	1
ventricular zone	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
right testis	1
bone marrow cell	1
calcaneal tendon	1
cortical plate	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLD1	134	ubiquitous	marker	mucosa of transverse colon, ventricular zone, primordial germ cell in gonad
POLE	221	ubiquitous	marker	right hemisphere of cerebellum, right testis, cerebellar hemisphere
EXOC4	261	ubiquitous	marker	bone marrow cell, cortical plate, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLD1	4,000
POLE	3,267
EXOC4	2,865

Intra-cohort edges

A	B	Sources
POLD1	POLE	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLE	Q07864	18
POLD1	P28340	6
EXOC4	Q96A65	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
PCNA-Dependent Long Patch Base Excision Repair	2	346.1×	1e-04	POLD1, POLE
Gap-filling DNA repair synthesis and ligation in GG-NER	2	292.8×	1e-04	POLD1, POLE
Recognition of DNA damage by PCNA-containing replication complex	2	253.8×	1e-04	POLD1, POLE
Termination of translesion DNA synthesis	2	230.7×	1e-04	POLD1, POLE
Dual Incision in GG-NER	2	173.0×	2e-04	POLD1, POLE
HDR through Homologous Recombination (HRR)	2	126.9×	3e-04	POLD1, POLE
Gap-filling DNA repair synthesis and ligation in TC-NER	2	119.0×	3e-04	POLD1, POLE
Dual incision in TC-NER	2	115.3×	3e-04	POLD1, POLE
DNA replication initiation	1	475.8×	0.005	POLE
Processive synthesis on the lagging strand	1	380.7×	0.005	POLD1
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)	1	271.9×	0.005	POLD1
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	1	271.9×	0.005	POLD1
Polymerase switching	1	271.9×	0.005	POLD1
Removal of the Flap Intermediate	1	271.9×	0.005	POLD1
Processive synthesis on the C-strand of the telomere	1	253.8×	0.005	POLD1
Telomere C-strand (Lagging Strand) Synthesis	1	253.8×	0.005	POLD1
Cytosolic iron-sulfur cluster assembly	1	253.8×	0.005	POLD1
Removal of the Flap Intermediate from the C-strand	1	211.5×	0.006	POLD1
VxPx cargo-targeting to cilium	1	173.0×	0.007	EXOC4
Insulin processing	1	152.3×	0.008	EXOC4
Polymerase switching on the C-strand of the telomere	1	141.0×	0.008	POLD1
Activation of the pre-replicative complex	1	108.8×	0.010	POLE
Translocation of SLC2A4 (GLUT4) to the plasma membrane	1	51.4×	0.019	EXOC4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
DNA replication proofreading	2	3744.9×	2e-06	POLD1, POLE
nucleotide-excision repair, DNA gap filling	2	1872.4×	4e-06	POLD1, POLE
base-excision repair, gap-filling	2	749.0×	2e-05	POLD1, POLE
DNA synthesis involved in DNA repair	2	624.1×	2e-05	POLD1, POLE
DNA-templated DNA replication	2	374.5×	5e-05	POLD1, POLE
DNA replication	2	110.1×	5e-04	POLD1, POLE
leading strand elongation	1	1404.3×	0.003	POLE
paraxial mesoderm formation	1	1123.5×	0.003	EXOC4
error-free translesion synthesis	1	1123.5×	0.003	POLD1
obsolete vesicle tethering involved in exocytosis	1	624.1×	0.004	EXOC4
protein transmembrane transport	1	432.1×	0.005	EXOC4
fatty acid homeostasis	1	312.1×	0.007	POLD1
DNA biosynthetic process	1	267.5×	0.007	POLD1
obsolete vesicle docking involved in exocytosis	1	224.7×	0.008	EXOC4
Golgi to plasma membrane transport	1	187.2×	0.009	EXOC4
embryonic organ development	1	160.5×	0.010	POLE
membrane fission	1	137.0×	0.011	EXOC4
response to UV	1	122.1×	0.012	POLD1
regulation of macroautophagy	1	98.5×	0.013	EXOC4
cellular response to UV	1	98.5×	0.013	POLD1
mitotic cytokinesis	1	86.4×	0.014	EXOC4
G1/S transition of mitotic cell cycle	1	66.9×	0.018	POLE
exocytosis	1	50.6×	0.022	EXOC4
mitotic cell cycle	1	44.6×	0.024	POLE
chemical synaptic transmission	1	25.8×	0.040	EXOC4
DNA repair	1	21.3×	0.046	POLD1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POLD1	0	0
POLE	0	0
EXOC4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
POLD1	8	Binding:8
EXOC4	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
POLD1	2.7.7.7	DNA-directed DNA polymerase
POLE	2.7.7.7	DNA-directed DNA polymerase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	POLD1, POLE, EXOC4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
POLD1	8	—
POLE	0	—
EXOC4	1	—

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
NCT05367609	Not specified	RECRUITING	Personalized Perioperative Analgesia Platform (PPAP) for Pediatric Spine Fusion Surgery (sIRB)