Attenuated familial adenomatous polyposis

Summary

Attenuated familial adenomatous polyposis (MONDO:0016362) is a disease with 1 cohort gene and 4 clinical trials. Top therapeutic interventions include erlotinib and obeticholic acid.

At a glance

• Cohort genes: 1
• ClinVar variants: 5
• Phenotypes (HPO): 23
• Clinical trials: 4

Clinical features

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0200063	Colorectal polyposis	Very frequent (80-99%)
HP:0003003	Colon cancer	Frequent (30-79%)
HP:0004394	Multiple gastric polyps	Frequent (30-79%)
HP:0004783	Duodenal polyposis	Frequent (30-79%)
HP:0005227	Adenomatous colonic polyposis	Frequent (30-79%)
HP:0006753	Neoplasm of the stomach	Frequent (30-79%)
HP:0030255	Large intestinal polyposis	Frequent (30-79%)
HP:0100896	Rectal polyposis	Frequent (30-79%)
HP:0000131	Uterine leiomyoma	Occasional (5-29%)
HP:0000854	Thyroid adenoma	Occasional (5-29%)
HP:0005562	Multiple renal cysts	Occasional (5-29%)
HP:0009592	Astrocytoma	Occasional (5-29%)
HP:0010614	Fibroma	Occasional (5-29%)
HP:0012740	Papilloma	Occasional (5-29%)
HP:0040276	Adenocarcinoma of the colon	Occasional (5-29%)
HP:0007649	Congenital hypertrophy of retinal pigment epithelium	Excluded (0%)
HP:0002672	Gastrointestinal carcinoma	Very rare (<1-4%)
HP:0002894	Neoplasm of the pancreas	Very rare (<1-4%)
HP:0002895	Papillary thyroid carcinoma	Very rare (<1-4%)
HP:0003002	Breast carcinoma	Very rare (<1-4%)
HP:0006744	Adrenocortical carcinoma	Very rare (<1-4%)
HP:0008256	Adrenocortical adenoma	Very rare (<1-4%)
HP:0030434	Pilomatrixoma	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	attenuated familial adenomatous polyposis
Mondo ID	MONDO:0016362
MeSH	C538265
Orphanet	220460
ICD-11	1023083906
NCIT	C6729
SNOMED CT	715866009
UMLS	C2674616
MedGen	436213
GARD	0008532
Is cancer (heuristic)	no

Also known as: AAPC · AFAP · attenuated adenomatous polyposis coli · attenuated familial adenomatous polyposis · attenuated familial polyposis coli · attenuated FAP · hereditary flat adenoma syndrome · HFAS · mild form of FAP

Data availability: 5 ClinVar variants.

Disease family

An umbrella term covering 1 Mondo subtype.

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 › attenuated familial adenomatous polyposis

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

Subtypes (1): APC-related attenuated familial adenomatous polyposis

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

5 retrieved; paginated sample, class counts are floors:

3 conflicting classifications of pathogenicity, 2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
216159	NM_000038.6(APC):c.3299C>T (p.Ser1100Phe)	APC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
245699	NM_000038.6(APC):c.8402G>A (p.Arg2801Gln)	APC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
469929	NM_000038.6(APC):c.3629A>T (p.His1210Leu)	APC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
184702	NM_000038.6(APC):c.70C>T (p.Arg24Ter)	APC	Uncertain significance	reviewed by expert panel
655632	NC_000005.10:g.112707399A>G	APC	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
APC	Orphanet:220460	Attenuated familial adenomatous polyposis
APC	Orphanet:261584	5q22 microdeletion syndrome
APC	Orphanet:314022	Gastric adenocarcinoma and proximal polyposis of the stomach
APC	Orphanet:3258	Cenani-Lenz syndrome
APC	Orphanet:873	Desmoid tumor

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
APC	HGNC:583	ENSG00000134982	P25054	Adenomatous polyposis coli protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
APC	Adenomatous polyposis coli protein	Tumor suppressor.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
APC	Other/Unknown	no		Armadillo, APC_rpt, SAMP

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
medial globus pallidus	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
APC	297	ubiquitous	marker	substantia nigra pars compacta, substantia nigra pars reticulata, medial globus pallidus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APC	2,903

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APC	P25054	31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 31. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
APC truncation mutants are not K63 polyubiquitinated	1	11420.0×	0.003	APC
Signaling by AXIN mutants	1	1038.2×	0.003	APC
Signaling by CTNNB1 phospho-site mutants	1	1038.2×	0.003	APC
Signaling by APC mutants	1	1038.2×	0.003	APC
Signaling by AMER1 mutants	1	1038.2×	0.003	APC
APC truncation mutants have impaired AXIN binding	1	815.7×	0.003	APC
AXIN missense mutants destabilize the destruction complex	1	815.7×	0.003	APC
Truncations of AMER1 destabilize the destruction complex	1	815.7×	0.003	APC
Signaling by GSK3beta mutants	1	761.3×	0.003	APC
CTNNB1 S33 mutants aren’t phosphorylated	1	761.3×	0.003	APC
CTNNB1 S37 mutants aren’t phosphorylated	1	761.3×	0.003	APC
CTNNB1 S45 mutants aren’t phosphorylated	1	761.3×	0.003	APC
CTNNB1 T41 mutants aren’t phosphorylated	1	761.3×	0.003	APC
Beta-catenin phosphorylation cascade	1	671.8×	0.003	APC
Signaling by WNT in cancer	1	601.0×	0.003	APC
Apoptotic cleavage of cellular proteins	1	475.8×	0.004	APC
Apoptotic execution phase	1	475.8×	0.004	APC
Disassembly of the destruction complex and recruitment of AXIN to the membrane	1	356.9×	0.005	APC
Ovarian tumor domain proteases	1	278.5×	0.006	APC
Deactivation of the beta-catenin transactivating complex	1	233.1×	0.007	APC
Degradation of beta-catenin by the destruction complex	1	173.0×	0.008	APC
Apoptosis	1	167.9×	0.008	APC
Programmed Cell Death	1	146.4×	0.009	APC
Deubiquitination	1	124.1×	0.010	APC
TCF dependent signaling in response to WNT	1	117.7×	0.011	APC
Signaling by WNT	1	112.0×	0.011	APC
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.020	APC
Post-translational protein modification	1	19.2×	0.058	APC
Disease	1	13.1×	0.082	APC
Metabolism of proteins	1	12.4×	0.084	APC

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of microtubule-based movement	1	2808.7×	0.003	APC
negative regulation of cell cycle G1/S phase transition	1	2407.4×	0.003	APC
positive regulation of protein localization to centrosome	1	2407.4×	0.003	APC
negative regulation of cyclin-dependent protein serine/threonine kinase activity	1	2106.5×	0.003	APC
regulation of microtubule-based process	1	1872.4×	0.003	APC
regulation of attachment of spindle microtubules to kinetochore	1	1685.2×	0.003	APC
heart valve development	1	1532.0×	0.003	APC
positive regulation of pseudopodium assembly	1	1296.3×	0.003	APC
endocardial cushion morphogenesis	1	842.6×	0.004	APC
mitotic spindle assembly checkpoint signaling	1	561.7×	0.005	APC
cell fate specification	1	526.6×	0.005	APC
negative regulation of microtubule depolymerization	1	495.6×	0.005	APC
pattern specification process	1	468.1×	0.005	APC
negative regulation of G1/S transition of mitotic cell cycle	1	358.6×	0.006	APC
bicellular tight junction assembly	1	330.4×	0.006	APC
mitotic cytokinesis	1	259.3×	0.007	APC
insulin receptor signaling pathway	1	221.7×	0.008	APC
positive regulation of protein catabolic process	1	203.0×	0.008	APC
positive regulation of cold-induced thermogenesis	1	163.6×	0.010	APC
negative regulation of canonical Wnt signaling pathway	1	117.8×	0.013	APC
protein-containing complex assembly	1	113.9×	0.013	APC
Wnt signaling pathway	1	99.7×	0.014	APC
positive regulation of cell migration	1	61.7×	0.020	APC
cell migration	1	61.5×	0.020	APC
positive regulation of apoptotic process	1	56.7×	0.021	APC
DNA damage response	1	53.5×	0.021	APC
proteasome-mediated ubiquitin-dependent protein catabolic process	1	52.2×	0.021	APC
nervous system development	1	45.9×	0.023	APC
negative regulation of cell population proliferation	1	42.1×	0.025	APC
cell adhesion	1	37.5×	0.027	APC

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
APC	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
APC	24	Binding:24

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	APC

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
APC	24	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	2
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02961374	PHASE2	COMPLETED	Erlotinib Hydrochloride in Reducing Duodenal Polyp Burden in Patients With Familial Adenomatous Polyposis at Risk of Developing Colon Cancer
NCT05223036	PHASE2	TERMINATED	Testing Obeticholic Acid for Familial Adenomatous Polyposis
NCT07461246	Not specified	ACTIVE_NOT_RECRUITING	Familial Adenomatous Poliposys Italian Network (Rete Italiana Poliposi Adenomatosa Familiare)
NCT02747862	Not specified	COMPLETED	Non-Surgical Management of Attenuated and Deleterious (Classical) Familial Adenomatous Polyposis: A Long-term Surveillance Program

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ERLOTINIB	4	1
OBETICHOLIC ACID	4	1
CHEMBL4303680	0	1
CHEMBL5197244	0	1
CHEMBL5412701	0	1