Familial adenomatous polyposis 2

Summary

Familial adenomatous polyposis 2 (MONDO:0012041) is a disease caused by MUTYH (GenCC Definitive), with 7 cohort genes and 4 clinical trials.

At a glance

• Causal gene: MUTYH (GenCC Definitive)
• Cohort genes: 7
• ClinVar variants: 2,490
• Phenotypes (HPO): 7
• Clinical trials: 4

Clinical features

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0200063	Colorectal polyposis	Very frequent (80-99%)
HP:0005227	Adenomatous colonic polyposis	Frequent (30-79%)
HP:0030255	Large intestinal polyposis	Frequent (30-79%)
HP:0040276	Adenocarcinoma of the colon	Frequent (30-79%)
HP:0100896	Rectal polyposis	Frequent (30-79%)
HP:0100245	Desmoid tumors	Excluded (0%)
HP:0007649	Congenital hypertrophy of retinal pigment epithelium	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial adenomatous polyposis 2
Mondo ID	MONDO:0012041
MeSH	C563924
OMIM	608456
Orphanet	247798
DOID	DOID:0080410
NCIT	C96520
UMLS	C3272841
MedGen	474474
GARD	0010805
Is cancer (heuristic)	no

Also known as: adenomas, multiple colorectal, autosomal recessive · autosomal recessive familial adenomatous polyposis · autosomal recessive multiple colorectal adenomas · colorectal adenomatous polyposis, autosomal recessive · familial adenomatous polyposis 2 · familial adenomatous polyposis, 2 · familial adenomatous polyposis, type 2 · FAP2 · MAP · MAP syndrome · MUTYH-associated polyposis · MUTYH-related adenomatous polyposis · MUTYH-related AFAP · MYH-associated polyposis

Data availability: 2,490 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › familial adenomatous polyposis 2

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

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:

185 likely benign, 170 conflicting classifications of pathogenicity, 162 uncertain significance, 37 pathogenic, 22 pathogenic/likely pathogenic, 17 likely pathogenic, 6 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1455311	NC_000001.10:g.(?45793451)(45798111_?)del	HPDL	Pathogenic	criteria provided, single submitter
1002182	NM_001048174.2(MUTYH):c.1435-2A>T	MUTYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1045946	NM_001048174.2(MUTYH):c.764_772del (p.Met255_Gly258delinsArg)	MUTYH	Pathogenic	criteria provided, single submitter
1050536	NM_001048174.2(MUTYH):c.1393-51_*2del	MUTYH	Pathogenic	no assertion criteria provided
1068517	NM_001048174.2(MUTYH):c.811C>T (p.Gln271Ter)	MUTYH	Pathogenic	criteria provided, single submitter
1069525	NM_001048174.2(MUTYH):c.775dup (p.Ala259fs)	MUTYH	Pathogenic	criteria provided, multiple submitters, no conflicts
1070115	NM_001048174.2(MUTYH):c.507del (p.Gly171fs)	MUTYH	Pathogenic	criteria provided, multiple submitters, no conflicts
1070581	NM_001048174.2(MUTYH):c.148C>T (p.Gln50Ter)	MUTYH	Pathogenic	criteria provided, multiple submitters, no conflicts
1072128	NM_001048174.2(MUTYH):c.1425del (p.Thr476fs)	MUTYH	Pathogenic	criteria provided, single submitter
1072724	NM_001048174.2(MUTYH):c.914-1G>T	MUTYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075894	NM_001048174.2(MUTYH):c.310dup (p.Val104fs)	MUTYH	Pathogenic	criteria provided, single submitter
1076845	NM_001048174.2(MUTYH):c.376_377del (p.Gln126fs)	MUTYH	Pathogenic	criteria provided, multiple submitters, no conflicts
127831	NM_001048174.2(MUTYH):c.1143_1144dup (p.Glu382fs)	MUTYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
127835	NM_001048174.2(MUTYH):c.928C>T (p.Gln310Ter)	MUTYH	Pathogenic	criteria provided, multiple submitters, no conflicts
127838	NM_001048174.2(MUTYH):c.1350GGA[1] (p.Glu452del)	MUTYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
127845	NM_001048174.2(MUTYH):c.13C>T (p.Arg5Ter)	MUTYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
134860	NM_001048174.2(MUTYH):c.1063del (p.Ala357fs)	MUTYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1352487	NM_001048174.2(MUTYH):c.409del (p.Ala137fs)	MUTYH	Pathogenic	criteria provided, single submitter
1356072	NM_001128425.2(MUTYH):c.177_178insCA (p.Glu60fs)	MUTYH	Pathogenic	criteria provided, single submitter
135990	NM_001048174.2(MUTYH):c.652G>T (p.Val218Phe)	MUTYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
135992	NM_001048174.2(MUTYH):c.849+3A>C	MUTYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1364709	NM_001048174.2(MUTYH):c.924_925del (p.Gly309fs)	MUTYH	Pathogenic	criteria provided, single submitter
1368442	NM_001048174.2(MUTYH):c.541C>T (p.Gln181Ter)	MUTYH	Pathogenic	criteria provided, multiple submitters, no conflicts
1374111	NM_001048174.2(MUTYH):c.779_780del (p.Thr260fs)	MUTYH	Pathogenic	criteria provided, single submitter
1395788	NM_001048174.2(MUTYH):c.136del (p.Glu46fs)	MUTYH	Pathogenic	criteria provided, single submitter
140811	NM_001048174.2(MUTYH):c.309G>A (p.Trp103Ter)	MUTYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1408238	NM_001048174.2(MUTYH):c.1276C>T (p.Gln426Ter)	MUTYH	Pathogenic	criteria provided, single submitter
140827	NM_001048174.2(MUTYH):c.205C>T (p.Arg69Ter)	MUTYH	Pathogenic	criteria provided, multiple submitters, no conflicts
140874	NM_001048174.2(MUTYH):c.1102+1G>A	MUTYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
140876	NM_001048174.2(MUTYH):c.856C>T (p.Gln286Ter)	MUTYH	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 14 · 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
MUTYH	Definitive	Autosomal recessive	familial adenomatous polyposis 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MUTYH	Orphanet:247798	MUTYH-related polyposis
MUTYH	Orphanet:440437	Familial colorectal cancer Type X
VDR	Orphanet:93160	Hypocalcemic vitamin D-resistant rickets
TOE1	Orphanet:284339	Pontocerebellar hypoplasia type 7
RABL3	Orphanet:1333	Familial pancreatic carcinoma
HPDL	Orphanet:528084	Non-specific syndromic intellectual disability
HPDL	Orphanet:631076	Autosomal recessive spastic paraplegia type 83
HPDL	Orphanet:641353	Infantile neurodegeneration-progressive spasticity-intellectual disability-white matter lesions syndrome
EIF2B3	Orphanet:157713	Congenital or early infantile CACH syndrome
EIF2B3	Orphanet:157716	Late infantile CACH syndrome
EIF2B3	Orphanet:157719	Juvenile or adult CACH syndrome
EIF2B3	Orphanet:99853	Ovarioleukodystrophy
EIF2B3	Orphanet:99854	Cree leukoencephalopathy
BARD1	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MUTYH	HGNC:7527	ENSG00000132781	Q9UIF7	Adenine DNA glycosylase	gencc,clinvar
VDR	HGNC:12679	ENSG00000111424	P11473	Vitamin D3 receptor	clinvar
TOE1	HGNC:15954	ENSG00000132773	Q96GM8	Target of EGR1 protein 1	clinvar
RABL3	HGNC:18072	ENSG00000144840	Q5HYI8	Rab-like protein 3	clinvar
HPDL	HGNC:28242	ENSG00000186603	Q96IR7	4-hydroxyphenylpyruvate dioxygenase-like protein	clinvar
EIF2B3	HGNC:3259	ENSG00000070785	Q9NR50	Translation initiation factor eIF2B subunit gamma	clinvar
BARD1	HGNC:952	ENSG00000138376	Q99728	BRCA1-associated RING domain protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MUTYH	Adenine DNA glycosylase	Involved in oxidative DNA damage repair.
VDR	Vitamin D3 receptor	Nuclear receptor for calcitriol, the active form of vitamin D3 which mediates the action of this vitamin on cells.
TOE1	Target of EGR1 protein 1	Inhibits cell growth rate and cell cycle.
RABL3	Rab-like protein 3	Small GTPase required for KRAS signaling regulation and modulation of cell proliferation.
HPDL	4-hydroxyphenylpyruvate dioxygenase-like protein	Iron-dependent dioxygenase that catalyzes the conversion of 4-hydroxyphenylpyruvate (4-HPPA) to 4-hydroxymandelate (4-HMA) in the mitochondria, one of the steps in the biosynthesis of coenzyme Q10 from tyrosine.
EIF2B3	Translation initiation factor eIF2B subunit gamma	Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on the eukaryotic initiation factor 2 (eIF2) complex gamma subunit.
BARD1	BRCA1-associated RING domain protein 1	E3 ubiquitin-protein ligase.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 4 · Druggable fraction: 0.14

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
Nuclear receptor	1	55.1×	0.054
Transcription factor	2	2.4×	0.306
Other/Unknown	4	1.0×	0.626

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MUTYH	Other/Unknown	no		NUDIX_hydrolase_dom, HhH_motif, HhH-GPD_domain
VDR	Nuclear receptor	yes		VitD_rcpt, Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt
TOE1	Transcription factor	no		Znf_CCCH, RNase_CAF1, RNaseH-like_sf
RABL3	Other/Unknown	no		P-loop_NTPase
HPDL	Other/Unknown	no		4OHPhenylPyrv_dOase, Glyas_Bleomycin-R_OHBP_Dase, VOC_core
EIF2B3	Other/Unknown	no		NTP_transferase_dom, Nucleotide-diphossugar_trans, eIF2B_gamma
BARD1	Transcription factor	no	2.3.2.27	BRCT_dom, Znf_RING, Ankyrin_rpt

Expression context

Cohort genes with no expression data: 0.

6 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	2
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
hair follicle	1
jejunal mucosa	1
tibia	1
olfactory bulb	1
type B pancreatic cell	1
adrenal tissue	1
islet of Langerhans	1
rectum	1
ileal mucosa	1
mucosa of transverse colon	1
gastrocnemius	1
gluteal muscle	1
triceps brachii	1
oocyte	1
secondary oocyte	1
tongue squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MUTYH	134	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
VDR	224	ubiquitous	marker	tibia, hair follicle, jejunal mucosa
TOE1	268	ubiquitous	yes	type B pancreatic cell, olfactory bulb, primordial germ cell in gonad
RABL3	278	ubiquitous	marker	adrenal tissue, islet of Langerhans, rectum
HPDL	152	broad	marker	primordial germ cell in gonad, mucosa of transverse colon, ileal mucosa
EIF2B3	271	ubiquitous	marker	triceps brachii, gluteal muscle, gastrocnemius
BARD1	271	ubiquitous	marker	secondary oocyte, oocyte, tongue squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BARD1	4,230
EIF2B3	3,212
RABL3	3,127
TOE1	1,867
MUTYH	1,815
HPDL	1,149
VDR	354

Intra-cohort edges

A	B	Sources
MUTYH	TOE1	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VDR	P11473	52
EIF2B3	Q9NR50	26
BARD1	Q99728	11
MUTYH	Q9UIF7	3
TOE1	Q96GM8	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HPDL	Q96IR7	91.45
RABL3	Q5HYI8	81.14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 52. Enrichment computed across 7 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective MUTYH substrate binding	1	2284.0×	0.011	MUTYH
Defective MUTYH substrate processing	1	2284.0×	0.011	MUTYH
Defective DNA double strand break response due to BRCA1 loss of function	1	1142.0×	0.011	BARD1
Defective DNA double strand break response due to BARD1 loss of function	1	1142.0×	0.011	BARD1
Recycling of eIF2:GDP	1	253.8×	0.029	EIF2B3
Displacement of DNA glycosylase by APEX1	1	207.6×	0.029	MUTYH
Defective homologous recombination repair (HRR) due to PALB2 loss of function	1	190.3×	0.029	BARD1
Vitamin D (calciferol) metabolism	1	175.7×	0.029	VDR
Ubiquinol biosynthesis	1	175.7×	0.029	HPDL
Diseases of DNA Double-Strand Break Repair	1	163.1×	0.029	BARD1
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1	163.1×	0.029	BARD1
Resolution of D-Loop Structures	1	126.9×	0.033	BARD1
Diseases of DNA repair	1	114.2×	0.033	BARD1
DNA Double Strand Break Response	1	95.2×	0.033	BARD1
Impaired BRCA2 binding to PALB2	1	91.4×	0.033	BARD1
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	84.6×	0.033	BARD1
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	84.6×	0.033	BARD1
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	84.6×	0.033	BARD1
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	78.8×	0.033	BARD1
Homologous DNA Pairing and Strand Exchange	1	76.1×	0.033	BARD1
SUMOylation of intracellular receptors	1	67.2×	0.033	VDR
Homology Directed Repair	1	61.7×	0.033	BARD1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	61.7×	0.033	BARD1
Impaired BRCA2 binding to RAD51	1	61.7×	0.033	BARD1
Metalloprotease DUBs	1	60.1×	0.033	BARD1
Resolution of D-loop Structures through Holliday Junction Intermediates	1	60.1×	0.033	BARD1
HDR through Single Strand Annealing (SSA)	1	58.6×	0.033	BARD1
Presynaptic phase of homologous DNA pairing and strand exchange	1	54.4×	0.034	BARD1
DNA Double-Strand Break Repair	1	49.6×	0.036	BARD1
Recognition and association of DNA glycosylase with site containing an affected purine	1	40.8×	0.040	MUTYH

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of mRNA 3’-end processing	1	2407.4×	0.011	BARD1
regulation of protein lipidation	1	2407.4×	0.011	RABL3
aromatic amino acid metabolic process	1	1203.7×	0.011	HPDL
nuclear receptor-mediated bile acid signaling pathway	1	1203.7×	0.011	VDR
response to bile acid	1	1203.7×	0.011	VDR
apoptotic process involved in mammary gland involution	1	802.5×	0.013	VDR
depurination	1	601.9×	0.013	MUTYH
positive regulation of apoptotic process involved in mammary gland involution	1	601.9×	0.013	VDR
mammary gland branching involved in pregnancy	1	601.9×	0.013	VDR
regulation of phosphorylation	1	401.2×	0.014	BARD1
vitamin D receptor signaling pathway	1	401.2×	0.014	VDR
positive regulation of vitamin D receptor signaling pathway	1	401.2×	0.014	VDR
negative regulation of protein export from nucleus	1	300.9×	0.016	BARD1
DNA strand resection involved in replication fork processing	1	300.9×	0.016	BARD1
regulation of Ras protein signal transduction	1	267.5×	0.017	RABL3
cytoplasmic translational initiation	1	200.6×	0.019	EIF2B3
homologous recombination	1	200.6×	0.019	BARD1
snRNA 3’-end processing	1	185.2×	0.019	TOE1
phosphate ion transmembrane transport	1	172.0×	0.019	VDR
intestinal absorption	1	172.0×	0.019	VDR
DNA repair	2	18.2×	0.019	MUTYH, BARD1
regulation of DNA damage checkpoint	1	160.5×	0.019	BARD1
intracellular receptor signaling pathway	1	141.6×	0.019	VDR
negative regulation of necroptotic process	1	141.6×	0.019	MUTYH
protein K6-linked ubiquitination	1	141.6×	0.019	BARD1
natural killer cell differentiation	1	126.7×	0.021	RABL3
mitotic G2/M transition checkpoint	1	114.6×	0.021	BARD1
positive regulation of keratinocyte differentiation	1	114.6×	0.021	VDR
positive regulation of cilium assembly	1	109.4×	0.022	RABL3
negative regulation of keratinocyte proliferation	1	100.3×	0.022	VDR

Therapeutics

Drug target analysis

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

Druggability breadth: 5 of 7 evidence-associated genes (71%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
VDR	CHOLECALCIFEROL
RABL3	GILTERITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VDR	10	4
TOE1	1	2
RABL3	1	4
MUTYH	0	0
HPDL	0	0
EIF2B3	0	0
BARD1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CHOLECALCIFEROL	4	VDR
CALCIPOTRIENE	4	VDR
DOXERCALCIFEROL	4	VDR
TACALCITOL	4	VDR
CALCITRIOL	4	VDR
GILTERITINIB	4	RABL3
CURCUMIN	3	VDR
SEOCALCITOL	3	VDR
MAXACALCITOL	3	VDR
TAUROLITHOCHOLIC ACID	3	VDR
MOLIBRESIB	2	TOE1
TRICHOSTATIN	1	VDR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
VDR	561	Binding:459, Functional:99, ADMET:3
EIF2B3	9	Binding:9
TOE1	6	Binding:6
RABL3	2	Binding:2
MUTYH	1	Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BARD1	2.3.2.27	RING-type E3 ubiquitin transferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
VDR	561

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

12 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.

Compound	Max phase	Cohort target (bioactivity)
CHOLECALCIFEROL	4	VDR
CALCIPOTRIENE	4	VDR
DOXERCALCIFEROL	4	VDR
TACALCITOL	4	VDR
CALCITRIOL	4	VDR
GILTERITINIB	4	RABL3
CURCUMIN	3	VDR
SEOCALCITOL	3	VDR
MAXACALCITOL	3	VDR
TAUROLITHOCHOLIC ACID	3	VDR
MOLIBRESIB	2	TOE1
TRICHOSTATIN	1	VDR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	VDR, RABL3
B	Phased (≥1) drug, not yet approved	1	TOE1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	MUTYH, HPDL, EIF2B3, BARD1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MUTYH	1	—
HPDL	0	—
EIF2B3	9	—
BARD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07461246	Not specified	ACTIVE_NOT_RECRUITING	Familial Adenomatous Poliposys Italian Network (Rete Italiana Poliposi Adenomatosa Familiare)
NCT02198092	Not specified	COMPLETED	Preliminary Evaluation of Septin9 in Patients With Hereditary Colon Cancer Syndromes
NCT03847532	Not specified	UNKNOWN	MUTYH-associated Polyposis
NCT06163365	Not specified	UNKNOWN	Inherited Cancer Early Diagnosis (ICED) Study