Familial adenomatous polyposis 3

Summary

Familial adenomatous polyposis 3 (MONDO:0014630) is a disease caused by NTHL1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: NTHL1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 289
• Phenotypes (HPO): 15

Clinical features

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0005227	Adenomatous colonic polyposis	Very frequent (80-99%)
HP:0002858	Meningioma	Frequent (30-79%)
HP:0003002	Breast carcinoma	Frequent (30-79%)
HP:0003003	Colon cancer	Frequent (30-79%)
HP:0008069	Neoplasm of the skin	Frequent (30-79%)
HP:0009725	Bladder neoplasm	Frequent (30-79%)
HP:0012114	Endometrial carcinoma	Frequent (30-79%)
HP:0100743	Neoplasm of the rectum	Frequent (30-79%)
HP:0000138	Ovarian cyst	Occasional (5-29%)
HP:0002671	Basal cell carcinoma	Occasional (5-29%)
HP:0002860	Squamous cell carcinoma	Occasional (5-29%)
HP:0006725	Pancreatic adenocarcinoma	Occasional (5-29%)
HP:0006771	Duodenal adenocarcinoma	Occasional (5-29%)
HP:0012539	Non-Hodgkin lymphoma	Occasional (5-29%)
HP:0031287	Seborrheic keratosis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial adenomatous polyposis 3
Mondo ID	MONDO:0014630
OMIM	616415
Orphanet	454840
DOID	DOID:0080411
UMLS	C4225157
MedGen	902388
GARD	0017790
Is cancer (heuristic)	no

Also known as: familial adenomatous polyposis 3 · familial adenomatous polyposis type 3 · FAP3 · NTHL1-related AFAP · NTHL1-related attenuated familial adenomatous polyposis · NTHL1-related attenuated FAP

Data availability: 289 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 › hereditary neoplastic syndrome › intestinal polyposis syndrome › classic or attenuated familial adenomatous polyposis › familial adenomatous polyposis 3

Related subtypes (7): familial adenomatous polyposis 2, 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

289 retrieved; paginated sample, class counts are floors:

131 uncertain significance, 54 pathogenic, 50 conflicting classifications of pathogenicity, 26 pathogenic/likely pathogenic, 12 likely benign, 12 likely pathogenic, 2 benign/likely benign, 1 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068685	NM_002528.7(NTHL1):c.510del (p.Val171fs)	NTHL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070434	NM_002528.7(NTHL1):c.265dup (p.Val89fs)	NTHL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1074525	NM_002528.7(NTHL1):c.307dup (p.Asp103fs)	NTHL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1074540	NM_002528.7(NTHL1):c.84del (p.Pro30fs)	NTHL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1075052	NM_002528.7(NTHL1):c.160_161del (p.Gln54fs)	NTHL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1076395	NM_002528.7(NTHL1):c.736A>T (p.Lys246Ter)	NTHL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1177373	NM_002528.7(NTHL1):c.745A>T (p.Lys249Ter)	NTHL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1381420	NM_002528.7(NTHL1):c.526-1G>T	NTHL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1405525	NM_002528.7(NTHL1):c.256C>T (p.Gln86Ter)	NTHL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1415037	NM_002528.7(NTHL1):c.418dup (p.Ala140fs)	NTHL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1452364	NM_002528.7(NTHL1):c.568C>T (p.Gln190Ter)	NTHL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1484387	NM_002528.7(NTHL1):c.675_676del (p.Ser226fs)	NTHL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1515221	NM_002528.7(NTHL1):c.709dup (p.Ile237fs)	NTHL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1515250	NM_002528.7(NTHL1):c.625_626del (p.Val209fs)	NTHL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1741266	NM_002528.7(NTHL1):c.428dup (p.Met143fs)	NTHL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1776794	NM_002528.7(NTHL1):c.138del (p.Pro46_Val47insTer)	NTHL1	Pathogenic	criteria provided, multiple submitters, no conflicts
2020379	NM_002528.7(NTHL1):c.666G>A (p.Trp222Ter)	NTHL1	Pathogenic	criteria provided, multiple submitters, no conflicts
2025416	NM_002528.7(NTHL1):c.226del (p.Val76fs)	NTHL1	Pathogenic	criteria provided, multiple submitters, no conflicts
2135297	NM_002528.7(NTHL1):c.469del (p.Leu157fs)	NTHL1	Pathogenic	criteria provided, multiple submitters, no conflicts
2169584	NM_002528.7(NTHL1):c.521G>A (p.Trp174Ter)	NTHL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218092	NM_002528.7(NTHL1):c.685+1G>A	NTHL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2194859	NM_002528.7(NTHL1):c.800G>A (p.Trp267Ter)	NTHL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2431314	NM_002528.7(NTHL1):c.199A>T (p.Lys67Ter)	NTHL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2431325	NM_002528.7(NTHL1):c.185del (p.Gly62fs)	NTHL1	Pathogenic	criteria provided, single submitter
2673803	NM_002528.7(NTHL1):c.322G>T (p.Glu108Ter)	NTHL1	Pathogenic	criteria provided, single submitter
2673804	NM_002528.7(NTHL1):c.34_53dup (p.Pro21fs)	NTHL1	Pathogenic	criteria provided, multiple submitters, no conflicts
2673805	NM_002528.7(NTHL1):c.565C>T (p.Gln189Ter)	NTHL1	Pathogenic	criteria provided, multiple submitters, no conflicts
2673806	NM_002528.7(NTHL1):c.-9G>T	NTHL1	Pathogenic	criteria provided, single submitter
2673807	NM_002528.7(NTHL1):c.805G>T (p.Glu269Ter)	NTHL1	Pathogenic	criteria provided, single submitter
2673808	NM_002528.7(NTHL1):c.559_562del (p.Ile187fs)	NTHL1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · 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
NTHL1	Definitive	Autosomal recessive	familial adenomatous polyposis 3	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NTHL1	Orphanet:454840	NTHL1-related polyposis

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
NTHL1	HGNC:8028	ENSG00000065057	P78549	Endonuclease III-like protein 1	gencc,clinvar
BRICD5	HGNC:28309	ENSG00000182685	Q6PL45	BRICHOS domain-containing protein 5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NTHL1	Endonuclease III-like protein 1	Bifunctional DNA N-glycosylase with associated apurinic/apyrimidinic (AP) lyase function that catalyzes the first step in base excision repair (BER), the primary repair pathway for the repair of oxidative DNA damage.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NTHL1	Enzyme (other)	yes	4.2.99.18	HhH_motif, HhH-GPD_domain, Endonuclease3_FeS-loop_motif
BRICD5	Other/Unknown	no		BRICHOS_dom, Gastrokine

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
mucosa of transverse colon	1
right lobe of liver	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NTHL1	211	ubiquitous	marker	right lobe of liver, apex of heart, mucosa of transverse colon
BRICD5	164		yes	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NTHL1	1,994
BRICD5	447

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NTHL1	P78549	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BRICD5	Q6PL45	70.89

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 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
Defective NTHL1 substrate processing	1	11420.0×	2e-04	NTHL1
Defective NTHL1 substrate binding	1	11420.0×	2e-04	NTHL1
Displacement of DNA glycosylase by APEX1	1	1038.2×	0.002	NTHL1
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	1	184.2×	0.005	NTHL1
Cleavage of the damaged pyrimidine	1	184.2×	0.005	NTHL1

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
base-excision repair, AP site formation	1	1685.2×	0.002	NTHL1
depyrimidination	1	936.2×	0.002	NTHL1
nucleotide-excision repair	1	191.5×	0.007	NTHL1
regulation of cell population proliferation	1	57.7×	0.017	BRICD5

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
NTHL1	0	0
BRICD5	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
NTHL1	8	Binding:7, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NTHL1	4.2.99.18	DNA-(apurinic or apyrimidinic site) lyase

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	NTHL1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	BRICD5

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)
NTHL1	8	—
BRICD5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.