Familial adenomatous polyposis 4

Summary

Familial adenomatous polyposis 4 (MONDO:0044300) is a disease caused by MSH3 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MSH3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 545
• Phenotypes (HPO): 14

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0004784	Juvenile gastrointestinal polyposis	Very frequent (80-99%)
HP:0005227	Adenomatous colonic polyposis	Very frequent (80-99%)
HP:0200063	Colorectal polyposis	Very frequent (80-99%)
HP:0000131	Uterine leiomyoma	Frequent (30-79%)
HP:0000854	Thyroid adenoma	Frequent (30-79%)
HP:0003003	Colon cancer	Frequent (30-79%)
HP:0004394	Multiple gastric polyps	Frequent (30-79%)
HP:0008069	Neoplasm of the skin	Frequent (30-79%)
HP:0009592	Astrocytoma	Frequent (30-79%)
HP:0012126	Stomach cancer	Frequent (30-79%)
HP:0012740	Papilloma	Frequent (30-79%)
HP:0100743	Neoplasm of the rectum	Frequent (30-79%)
HP:0000107	Renal cyst	Occasional (5-29%)
HP:0025274	Ovarian dermoid cyst	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial adenomatous polyposis 4
Mondo ID	MONDO:0044300
OMIM	617100
Orphanet	480536
DOID	DOID:0080412
UMLS	C4310719
MedGen	934686
GARD	0017868
Is cancer (heuristic)	no

Also known as: familial adenomatous polyposis 4 · familial adenomatous polyposis type 4 · FAP4 · MSH3-related AFAP · MSH3-related attenuated familial adenomatous polyposis · MSH3-related attenuated familial polyposis coli · MSH3-related attenuated FAP

Data availability: 545 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 › hereditary neoplastic syndrome › intestinal polyposis syndrome › classic or attenuated familial adenomatous polyposis › familial adenomatous polyposis 4

Related subtypes (7): 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

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

545 retrieved; paginated sample, class counts are floors:

171 pathogenic, 131 uncertain significance, 90 pathogenic/likely pathogenic, 56 conflicting classifications of pathogenicity, 43 likely pathogenic, 24 likely benign, 23 benign/likely benign, 7 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070997	NM_002439.5(MSH3):c.76C>T (p.Arg26Ter)	DHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2673497	NM_002439.5(MSH3):c.85C>T (p.Gln29Ter)	DHFR	Pathogenic	criteria provided, single submitter
2673506	NM_002439.5(MSH3):c.36del (p.Ala13fs)	DHFR	Pathogenic	criteria provided, single submitter
2673531	NM_002439.5(MSH3):c.90dup (p.Thr31fs)	DHFR	Pathogenic	criteria provided, single submitter
2673556	NM_002439.5(MSH3):c.85del (p.Gln29fs)	DHFR	Pathogenic	criteria provided, single submitter
2673571	NM_002439.5(MSH3):c.61C>T (p.Gln21Ter)	DHFR	Pathogenic	criteria provided, single submitter
2676773	NM_002439.5(MSH3):c.96delinsCT (p.Gly32_Ser33insTer)	DHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
849780	NM_002439.5(MSH3):c.237+2T>C	DHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
940655	NM_002439.5(MSH3):c.14del (p.Lys5fs)	DHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1376058	NM_002439.5(MSH3):c.1022del (p.Gly341fs)	LOC126807437	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2018567	NM_002439.5(MSH3):c.957del (p.Asp320fs)	LOC126807437	Pathogenic	criteria provided, multiple submitters, no conflicts
2020610	NM_002439.5(MSH3):c.1017_1018insC (p.Ile340fs)	LOC126807437	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2673501	NM_002439.5(MSH3):c.971C>G (p.Ser324Ter)	LOC126807437	Pathogenic	criteria provided, single submitter
2673532	NM_002439.5(MSH3):c.930_931del (p.Glu311fs)	LOC126807437	Pathogenic	criteria provided, single submitter
2673546	NM_002439.5(MSH3):c.1014dup (p.Leu339fs)	LOC126807437	Pathogenic	criteria provided, single submitter
3148728	NM_002439.5(MSH3):c.993_994insTC (p.Ala332fs)	LOC126807437	Pathogenic	criteria provided, single submitter
657893	NM_002439.5(MSH3):c.978_984del (p.Phe326fs)	LOC126807437	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068348	NM_002439.5(MSH3):c.3001-1G>A	MSH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068925	NM_002439.5(MSH3):c.724C>T (p.Gln242Ter)	MSH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069054	NM_002439.5(MSH3):c.2835del (p.Tyr946fs)	MSH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069310	NM_002439.5(MSH3):c.1828C>T (p.Gln610Ter)	MSH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069698	NM_002439.5(MSH3):c.2420G>A (p.Trp807Ter)	MSH3	Pathogenic	criteria provided, multiple submitters, no conflicts
1070175	NM_002439.5(MSH3):c.2620C>T (p.Gln874Ter)	MSH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070750	NM_002439.5(MSH3):c.242del (p.Thr81fs)	MSH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071210	NM_002439.5(MSH3):c.263_267del (p.Lys88fs)	MSH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071655	NM_002439.5(MSH3):c.1686G>A (p.Trp562Ter)	MSH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071904	NM_002439.5(MSH3):c.2276_2277del (p.Ser759fs)	MSH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072005	NM_002439.5(MSH3):c.1428T>A (p.Tyr476Ter)	MSH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072068	NM_002439.5(MSH3):c.721C>T (p.Gln241Ter)	MSH3	Pathogenic	criteria provided, multiple submitters, no conflicts
1072147	NM_002439.5(MSH3):c.747T>A (p.Cys249Ter)	MSH3	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
MSH3	Definitive	Autosomal recessive	familial adenomatous polyposis 4	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MSH3	Orphanet:480536	MSH3-related polyposis
DHFR	Orphanet:319651	Constitutional megaloblastic anemia with severe neurologic disease

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
MSH3	HGNC:7326	ENSG00000113318	P20585	DNA mismatch repair protein Msh3	gencc,clinvar
DHFR	HGNC:2861	ENSG00000228716	P00374	Dihydrofolate reductase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MSH3	DNA mismatch repair protein Msh3	Component of the post-replicative DNA mismatch repair system (MMR).
DHFR	Dihydrofolate reductase	Catalyzes the reduction of 7,8-dihydrofolate (DHF) to 5,6,7,8-tetrahydrofolate in a NADPH-dependent manner.

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)
MSH3	Other/Unknown	no		DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS-lik_N, DNA_mismatch_repair_MutS_core
DHFR	Enzyme (other)	yes	1.5.1.3	DHFR_dom, DHFR, DHFR_CS

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	2
bronchial epithelial cell	1
mucosa of paranasal sinus	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MSH3	287	ubiquitous	marker	buccal mucosa cell, bronchial epithelial cell, mucosa of paranasal sinus
DHFR	290	ubiquitous	marker	buccal mucosa cell, ventricular zone, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DHFR	4,152
MSH3	2,276

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DHFR	P00374	89
MSH3	P20585	24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective Mismatch Repair Associated With MSH3	1	2855.0×	0.002	MSH3
Defective Mismatch Repair Associated With MSH2	1	1903.3×	0.002	MSH3
Mismatch Repair	1	1427.5×	0.002	MSH3
Diseases of Mismatch Repair (MMR)	1	1427.5×	0.002	MSH3
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation	1	571.0×	0.004	DHFR
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	1	407.9×	0.004	MSH3
Metabolism of folate and pterines	1	317.2×	0.005	DHFR
Diseases of DNA repair	1	285.5×	0.005	MSH3
G1/S-Specific Transcription	1	178.4×	0.007	DHFR
DNA Repair	1	49.2×	0.022	MSH3
Disease	1	6.5×	0.147	MSH3

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
response to methotrexate	1	8426.0×	0.001	DHFR
dihydrofolate metabolic process	1	2808.7×	0.001	DHFR
somatic recombination of immunoglobulin gene segments	1	2106.5×	0.001	MSH3
maintenance of DNA repeat elements	1	1685.2×	0.001	MSH3
mitotic recombination	1	1404.3×	0.001	MSH3
tetrahydrofolate biosynthetic process	1	1404.3×	0.001	DHFR
regulation of removal of superoxide radicals	1	1404.3×	0.001	DHFR
tetrahydrobiopterin biosynthetic process	1	1203.7×	0.001	DHFR
tetrahydrofolate metabolic process	1	1203.7×	0.001	DHFR
one-carbon metabolic process	1	561.7×	0.002	DHFR
axon regeneration	1	561.7×	0.002	DHFR
negative regulation of DNA recombination	1	561.7×	0.002	MSH3
folic acid metabolic process	1	561.7×	0.002	DHFR
mismatch repair	1	324.1×	0.004	MSH3
negative regulation of translation	1	98.0×	0.011	DHFR
DNA repair	1	31.9×	0.031	MSH3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
DHFR	TRIMETREXATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DHFR	23	4
MSH3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TRIMETREXATE	4	DHFR
PRALATREXATE	4	DHFR
LEUCOVORIN	4	DHFR
TRIMETHOPRIM	4	DHFR
RALTITREXED	4	DHFR
PEMETREXED	4	DHFR
METHOTREXATE	4	DHFR
PYRIMETHAMINE	4	DHFR
SULFADIAZINE	4	DHFR
SULFACETAMIDE	4	DHFR
GENTAMICIN	4	DHFR
MEFENAMIC ACID	4	DHFR
DIFLUNISAL	4	DHFR
TERIFLUNOMIDE	4	DHFR
ICLAPRIM	3	DHFR
DIAVERIDINE	2	DHFR
EPIROPRIM	2	DHFR
EDATREXATE	2	DHFR
AMINOPTERIN	2	DHFR
BREQUINAR	2	DHFR
CYCLOGUANIL	2	DHFR
PIRITREXIM	2	DHFR
FANOTAPRIM	1	DHFR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DHFR	457	Binding:426, ADMET:16, Functional:12, Toxicity:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DHFR	1.5.1.3	dihydrofolate reductase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
DHFR	457

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

23 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)
TRIMETREXATE	4	DHFR
PRALATREXATE	4	DHFR
LEUCOVORIN	4	DHFR
TRIMETHOPRIM	4	DHFR
RALTITREXED	4	DHFR
PEMETREXED	4	DHFR
METHOTREXATE	4	DHFR
PYRIMETHAMINE	4	DHFR
SULFADIAZINE	4	DHFR
SULFACETAMIDE	4	DHFR
GENTAMICIN	4	DHFR
MEFENAMIC ACID	4	DHFR
DIFLUNISAL	4	DHFR
TERIFLUNOMIDE	4	DHFR
ICLAPRIM	3	DHFR
DIAVERIDINE	2	DHFR
EPIROPRIM	2	DHFR
EDATREXATE	2	DHFR
AMINOPTERIN	2	DHFR
BREQUINAR	2	DHFR
CYCLOGUANIL	2	DHFR
PIRITREXIM	2	DHFR
FANOTAPRIM	1	DHFR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	DHFR
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	MSH3

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)
MSH3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.