Classic or attenuated familial adenomatous polyposis

Summary

Classic or attenuated familial adenomatous polyposis (MONDO:0021057) is a disease (an umbrella term covering 8 Mondo subtypes) caused by APC (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: APC (GenCC Definitive)
• Umbrella term: 8 Mondo subtypes
• Cohort genes: 1
• ClinVar variants: 1,928

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	classic or attenuated familial adenomatous polyposis
Mondo ID	MONDO:0021057
GARD	0025283
Is cancer (heuristic)	no

Also known as: classic or attenuated familial adenomatous polyposis · classic or attenuated FAP

Data availability: 1,928 ClinVar variants · 3 ClinGen variant curations · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 8 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

Related subtypes (7): Bannayan-Riley-Ruvalcaba syndrome, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, Cronkhite-Canada syndrome, hereditary mixed polyposis syndrome, hyperplastic polyposis syndrome, juvenile polyposis syndrome

Subtypes (8): familial adenomatous polyposis 2, familial adenomatous polyposis 3, attenuated familial adenomatous polyposis, AXIN2-related attenuated familial adenomatous polyposis, Polymerase proofreading-related adenomatous polyposis, classic familial adenomatous polyposis, familial adenomatous polyposis 1, familial adenomatous polyposis 4

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

600 retrieved; paginated sample, class counts are floors:

257 uncertain significance, 161 conflicting classifications of pathogenicity, 135 benign/likely benign, 20 likely benign, 11 pathogenic, 9 benign, 7 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068153	NM_000038.6(APC):c.1409-1G>C	APC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
127281	NM_000038.6(APC):c.2413C>T (p.Arg805Ter)	APC	Pathogenic	criteria provided, multiple submitters, no conflicts
127311	NM_000038.6(APC):c.6383del (p.Ala2128fs)	APC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
127312	NM_000038.6(APC):c.646C>T (p.Arg216Ter)	APC	Pathogenic	criteria provided, multiple submitters, no conflicts
141040	NM_000038.6(APC):c.935dup (p.Glu313fs)	APC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
141368	NM_000038.6(APC):c.147_150del (p.Lys49fs)	APC	Pathogenic	criteria provided, multiple submitters, no conflicts
142574	NM_000038.6(APC):c.426_427del (p.Leu143fs)	APC	Pathogenic	criteria provided, multiple submitters, no conflicts
1453360	NM_000038.6(APC):c.7927_7928del (p.Leu2643fs)	APC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456641	NM_000038.6(APC):c.6189_6190del (p.His2063fs)	APC	Pathogenic	criteria provided, multiple submitters, no conflicts
156479	NM_000038.6(APC):c.3814del (p.Ser1272fs)	APC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1750160	NM_000038.6(APC):c.5864del (p.Ala1955fs)	APC	Pathogenic	criteria provided, multiple submitters, no conflicts
181835	NM_000038.6(APC):c.5490_5493del (p.Asn1830fs)	APC	Pathogenic	criteria provided, multiple submitters, no conflicts
184117	NM_000038.6(APC):c.221-2A>G	APC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
187612	NM_000038.6(APC):c.6709C>T (p.Arg2237Ter)	APC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2081491	NM_000038.6(APC):c.2010dup (p.Ser671fs)	APC	Pathogenic	criteria provided, multiple submitters, no conflicts
217924	NM_000038.6(APC):c.1312+3A>G	APC	Pathogenic	reviewed by expert panel
2203686	NM_000038.6(APC):c.2522T>G (p.Leu841Ter)	APC	Pathogenic	criteria provided, multiple submitters, no conflicts
229997	NM_000038.6(APC):c.481C>T (p.Gln161Ter)	APC	Pathogenic	criteria provided, multiple submitters, no conflicts
1017874	NM_000038.6(APC):c.531T>C (p.Asn177=)	APC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1025685	NM_000038.6(APC):c.6481A>C (p.Ser2161Arg)	APC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1036972	NM_000038.6(APC):c.827A>G (p.Asn276Ser)	APC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1042757	NM_000038.6(APC):c.220+6T>C	APC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1046441	NM_000038.6(APC):c.6610C>G (p.Arg2204Gly)	APC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1134506	NM_000038.6(APC):c.6033A>T (p.Ser2011=)	APC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1171971	NM_000038.6(APC):c.4495G>C (p.Gly1499Arg)	APC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
127287	NM_000038.6(APC):c.3368A>C (p.Gln1123Pro)	APC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
127290	NM_000038.6(APC):c.3632T>C (p.Met1211Thr)	APC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
127297	NM_000038.6(APC):c.4709A>G (p.Asp1570Gly)	APC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
127298	NM_000038.6(APC):c.4766G>A (p.Arg1589His)	APC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
127301	NM_000038.6(APC):c.5017G>A (p.Glu1673Lys)	APC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 5 · 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
APC	Definitive	Autosomal dominant	familial adenomatous polyposis 1	15

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	gencc,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: 0.