Fanconi anemia

disease

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Also known as Fanconi pancytopeniaFanconi's anemiapancytopenia, congenitalPanmyelopathy, Fanconiprimary erythroid hypoplasia

Summary

Fanconi anemia (MONDO:0019391) is a disease (an umbrella term covering 22 Mondo subtypes) caused by variants in BRIP1 and FANCM, with 37 cohort genes and 84 clinical trials. The dominant Reactome pathway is Fanconi Anemia Pathway (13 cohort genes). Top therapeutic interventions include fludarabine phosphate, plerixafor, and alefacept.

At a glance

Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
Causal genes: BRIP1 (GenCC Definitive), FANCM (GenCC Strong)
Umbrella term: 22 Mondo subtypes
Cohort genes: 37
ClinVar variants: 16,760
Phenotypes (HPO): 106
Clinical trials: 84

Clinical features

Epidemiology

Prevalence records

7 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.3	Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.62	Europe	Validated
Point prevalence	1-9 / 100 000	3.3	Specific population	Validated
Point prevalence	1-9 / 100 000	2.5	Specific population	Validated
Point prevalence	1-9 / 1 000 000	0.111	China	Validated
Prevalence at birth	1-9 / 100 000	2.2	Israel	Validated

Signs & symptoms

Clinical features (HPO)

106 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001000	Abnormality of skin pigmentation	Very frequent (80-99%)
HP:0001053	Hypopigmented skin patches	Very frequent (80-99%)
HP:0001172	Abnormal thumb morphology	Very frequent (80-99%)
HP:0001871	Abnormality of blood and blood-forming tissues	Very frequent (80-99%)
HP:0001873	Thrombocytopenia	Very frequent (80-99%)
HP:0001882	Leukopenia	Very frequent (80-99%)
HP:0001903	Anemia	Very frequent (80-99%)
HP:0002817	Abnormality of the upper limb	Very frequent (80-99%)
HP:0003220	Abnormality of chromosome stability	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0005522	Pyridoxine-responsive sideroblastic anemia	Very frequent (80-99%)
HP:0006501	Aplasia/Hypoplasia of the radius	Very frequent (80-99%)
HP:0007400	Irregular hyperpigmentation	Very frequent (80-99%)
HP:0000079	Abnormality of the urinary system	Frequent (30-79%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001671	Abnormal cardiac septum morphology	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002664	Neoplasm	Frequent (30-79%)
HP:0007874	Almond-shaped palpebral fissure	Frequent (30-79%)
HP:0012210	Abnormal renal morphology	Frequent (30-79%)
HP:0012745	Short palpebral fissure	Frequent (30-79%)
HP:0000135	Hypogonadism	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000268	Dolichocephaly	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000324	Facial asymmetry	Occasional (5-29%)
HP:0000340	Sloping forehead	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000364	Hearing abnormality	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000453	Choanal atresia	Occasional (5-29%)
HP:0000478	Abnormality of the eye	Occasional (5-29%)
HP:0000483	Astigmatism	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000492	Abnormal eyelid morphology	Occasional (5-29%)
HP:0000504	Abnormality of vision	Occasional (5-29%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000520	Proptosis	Occasional (5-29%)
HP:0000568	Microphthalmia	Occasional (5-29%)
HP:0000582	Upslanted palpebral fissure	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000813	Bicornuate uterus	Occasional (5-29%)
HP:0000864	Abnormality of the hypothalamus-pituitary axis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Fanconi anemia
Mondo ID	MONDO:0019391
MeSH	D005199
OMIM	227650
Orphanet	84
DOID	DOID:13636
NCIT	C62505
SNOMED CT	30575002
UMLS	C0015625
MedGen	41967
GARD	0006425
MedDRA	10055206
NORD	1132
Is cancer (heuristic)	no

Also known as: Fanconi anemia · Fanconi pancytopenia · Fanconi’s anemia · pancytopenia, congenital · Panmyelopathy, Fanconi · primary erythroid hypoplasia

Data availability: 16,760 ClinVar variants · 26 GenCC gene-disease records · 198 cell lines.

Disease family

An umbrella term covering 22 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › congenital anemia › Fanconi anemia

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:

535 uncertain significance, 45 conflicting classifications of pathogenicity, 13 likely benign, 3 pathogenic, 2 pathogenic/likely pathogenic, 1 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1029499	NM_000135.4(FANCA):c.189+1G>T	FANCA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1045251	NM_000135.4(FANCA):c.4185dup (p.Ile1396fs)	FANCA	Pathogenic	criteria provided, multiple submitters, no conflicts
1050046	NM_000136.3(FANCC):c.1272G>A (p.Trp424Ter)	FANCC	Pathogenic	criteria provided, multiple submitters, no conflicts
1012833	NM_020937.4(FANCM):c.3898G>T (p.Glu1300Ter)	FANCM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1012390	NM_032444.4(SLX4):c.3916C>T (p.Gln1306Ter)	SLX4	Pathogenic	criteria provided, multiple submitters, no conflicts
1027625	NM_018062.4(FANCL):c.1051_1052dup (p.Ser351fs)	FANCL	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1017642	NM_000136.3(FANCC):c.1355A>G (p.His452Arg)	AOPEP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1053325	NM_000136.3(FANCC):c.1330-10T>C	AOPEP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1003552	NM_000135.4(FANCA):c.1951G>A (p.Gly651Arg)	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1007169	NM_000135.4(FANCA):c.1567-9T>A	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1009385	NM_000135.4(FANCA):c.1931A>G (p.Asn644Ser)	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1009909	NM_000135.4(FANCA):c.2982-8C>G	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1011326	NM_000135.4(FANCA):c.2109G>C (p.Gln703His)	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1015652	NM_000135.4(FANCA):c.2779-9C>G	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1019132	NM_000135.4(FANCA):c.4088A>G (p.Lys1363Arg)	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1021351	NM_000135.4(FANCA):c.837C>A (p.Asp279Glu)	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1023187	NM_000135.4(FANCA):c.166G>A (p.Asp56Asn)	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1025250	NM_000135.4(FANCA):c.2383A>G (p.Arg795Gly)	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1027038	NM_000135.4(FANCA):c.68C>T (p.Ala23Val)	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1035228	NM_000135.4(FANCA):c.2309G>A (p.Arg770His)	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1041108	NM_000135.4(FANCA):c.2786A>C (p.Tyr929Ser)	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1041618	NM_000135.4(FANCA):c.1237C>T (p.Arg413Cys)	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1042931	NM_000135.4(FANCA):c.2417C>T (p.Pro806Leu)	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1053079	NM_000135.4(FANCA):c.3610C>T (p.Arg1204Trp)	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1056321	NM_000135.4(FANCA):c.2622A>G (p.Arg874=)	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1059778	NM_000135.4(FANCA):c.2125C>G (p.Pro709Ala)	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1005025	NM_001018113.3(FANCB):c.800C>T (p.Ser267Leu)	FANCB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1045558	NM_001018113.3(FANCB):c.1838G>C (p.Arg613Pro)	FANCB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1047336	NM_001018113.3(FANCB):c.1226G>A (p.Arg409Gln)	FANCB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1054727	NM_001018113.3(FANCB):c.1267T>C (p.Tyr423His)	FANCB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 172 · Orphanet: 75 · 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
BRCA1	Definitive	Autosomal recessive	Fanconi anemia, complementation group S	11
BRCA2	Definitive	Autosomal recessive	Fanconi anemia complementation group D1	13
BRIP1	Definitive	Autosomal recessive	Fanconi anemia	10
FANCA	Definitive	Autosomal recessive	Fanconi anemia complementation group A	8
FANCB	Definitive	X-linked	Fanconi anemia complementation group B	7
FANCC	Definitive	Autosomal recessive	Fanconi anemia complementation group C	11
FANCD2	Definitive	Autosomal recessive	Fanconi anemia complementation group D2	6
FANCE	Definitive	Autosomal recessive	Fanconi anemia complementation group E	5
FANCF	Definitive	Autosomal recessive	Fanconi anemia complementation group F	5
FANCG	Definitive	Autosomal recessive	Fanconi anemia complementation group G	5
FANCI	Definitive	Autosomal recessive	Fanconi anemia complementation group I	6
FANCL	Definitive	Autosomal recessive	Fanconi anemia complementation group L	6
PALB2	Definitive	Autosomal recessive	Fanconi anemia complementation group N	9
SLX4	Definitive	Autosomal recessive	Fanconi anemia complementation group P	6
ERCC4	Strong	Autosomal recessive	Fanconi anemia complementation group Q	11
FANCM	Strong	Autosomal recessive	Fanconi anemia	10
RAD51	Strong	Autosomal dominant	Fanconi anemia complementation group R	10
RAD51C	Strong	Autosomal recessive	Fanconi anemia complementation group O	10
UBE2T	Strong	Autosomal recessive	Fanconi anemia complementation group T	4
RFWD3	Moderate	Autosomal recessive	Fanconi anemia, complementation group W	5
XRCC2	Moderate	Autosomal recessive	Fanconi anemia complementation group U	10
MAD2L2	Supportive	Autosomal recessive	Fanconi anemia	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BRCA2	Orphanet:1331	Familial prostate cancer
BRCA2	Orphanet:1333	Familial pancreatic carcinoma
BRCA2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRCA2	Orphanet:178	Chordoma
BRCA2	Orphanet:227535	Hereditary breast cancer
BRCA2	Orphanet:319462	Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations
BRCA2	Orphanet:440437	Familial colorectal cancer Type X
BRCA2	Orphanet:654	Nephroblastoma
BRCA2	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
BRCA2	Orphanet:694963	Inflammatory breast cancer
BRCA2	Orphanet:70567	Cholangiocarcinoma
BRCA2	Orphanet:84	Fanconi anemia
BRIP1	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRIP1	Orphanet:84	Fanconi anemia
FANCL	Orphanet:84	Fanconi anemia
FANCM	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
FANCM	Orphanet:84	Fanconi anemia
SLX4	Orphanet:84	Fanconi anemia
RFWD3	Orphanet:84	Fanconi anemia
FANCI	Orphanet:84	Fanconi anemia
PALB2	Orphanet:1333	Familial pancreatic carcinoma
PALB2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
PALB2	Orphanet:178	Chordoma
PALB2	Orphanet:227535	Hereditary breast cancer
PALB2	Orphanet:84	Fanconi anemia
FANCA	Orphanet:84	Fanconi anemia
FANCB	Orphanet:3412	VACTERL with hydrocephalus
FANCB	Orphanet:84	Fanconi anemia
FANCC	Orphanet:84	Fanconi anemia
FANCD2	Orphanet:84	Fanconi anemia
FANCE	Orphanet:84	Fanconi anemia
FANCF	Orphanet:84	Fanconi anemia
FANCG	Orphanet:84	Fanconi anemia
BRCA1	Orphanet:1331	Familial prostate cancer
BRCA1	Orphanet:1333	Familial pancreatic carcinoma
BRCA1	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRCA1	Orphanet:168829	Primary peritoneal carcinoma
BRCA1	Orphanet:227535	Hereditary breast cancer
BRCA1	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
BRCA1	Orphanet:694963	Inflammatory breast cancer
BRCA1	Orphanet:70567	Cholangiocarcinoma
BRCA1	Orphanet:84	Fanconi anemia
XRCC2	Orphanet:227535	Hereditary breast cancer
XRCC2	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
XRCC2	Orphanet:84	Fanconi anemia
UBE2T	Orphanet:84	Fanconi anemia
ERCC4	Orphanet:220295	Xeroderma pigmentosum-Cockayne syndrome complex
ERCC4	Orphanet:84	Fanconi anemia
ERCC4	Orphanet:90321	Cockayne syndrome type 1
ERCC4	Orphanet:910	Xeroderma pigmentosum

Cohort genes → proteins

37 cohort genes, 37 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	37

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BRCA2	HGNC:1101	ENSG00000139618	P51587	Breast cancer type 2 susceptibility protein	gencc,clinvar
BRIP1	HGNC:20473	ENSG00000136492	Q9BX63	Fanconi anemia group J protein	gencc,clinvar
FANCL	HGNC:20748	ENSG00000115392	Q9NW38	E3 ubiquitin-protein ligase FANCL	gencc,clinvar
FANCM	HGNC:23168	ENSG00000187790	Q8IYD8	Fanconi anemia group M protein	gencc,clinvar
SLX4	HGNC:23845	ENSG00000188827	Q8IY92	Structure-specific endonuclease subunit SLX4	gencc,clinvar
RFWD3	HGNC:25539	ENSG00000168411	Q6PCD5	E3 ubiquitin-protein ligase RFWD3	gencc,clinvar
FANCI	HGNC:25568	ENSG00000140525	Q9NVI1	Fanconi anemia group I protein	gencc,clinvar
PALB2	HGNC:26144	ENSG00000083093	Q86YC2	Partner and localizer of BRCA2	gencc,clinvar
FANCA	HGNC:3582	ENSG00000187741	O15360	Fanconi anemia group A protein	gencc,clinvar
FANCB	HGNC:3583	ENSG00000181544	Q8NB91	Fanconi anemia group B protein	gencc,clinvar
FANCC	HGNC:3584	ENSG00000158169	Q00597	Fanconi anemia group C protein	gencc,clinvar
FANCD2	HGNC:3585	ENSG00000144554	Q9BXW9	Fanconi anemia group D2 protein	gencc,clinvar
FANCE	HGNC:3586	ENSG00000112039	Q9HB96	Fanconi anemia group E protein	gencc,clinvar
FANCF	HGNC:3587	ENSG00000183161	Q9NPI8	Fanconi anemia group F protein	gencc,clinvar
FANCG	HGNC:3588	ENSG00000221829	O15287	Fanconi anemia group G protein	gencc,clinvar
BRCA1	HGNC:1100	ENSG00000012048	P38398	Breast cancer type 1 susceptibility protein	gencc
XRCC2	HGNC:12829	ENSG00000196584	O43543	DNA repair protein XRCC2	gencc
UBE2T	HGNC:25009	ENSG00000077152	Q9NPD8	Ubiquitin-conjugating enzyme E2 T	gencc
ERCC4	HGNC:3436	ENSG00000175595	Q92889	DNA repair endonuclease XPF	gencc
MAD2L2	HGNC:6764	ENSG00000116670	Q9UI95	Mitotic spindle assembly checkpoint protein MAD2B	gencc
RAD51	HGNC:9817	ENSG00000051180	Q06609	DNA repair protein RAD51 homolog 1	gencc
RAD51C	HGNC:9820	ENSG00000108384	O43502	DNA repair protein RAD51 homolog 3	gencc
VCP	HGNC:12666	ENSG00000165280	P55072	Transitional endoplasmic reticulum ATPase	clinvar
VRK2	HGNC:12719	ENSG00000028116	Q86Y07	Serine/threonine-protein kinase VRK2	clinvar
VPS9D1	HGNC:13526	ENSG00000075399	Q9Y2B5	VPS9 domain-containing protein 1	clinvar
ACE2	HGNC:13557	ENSG00000130234	Q9BYF1	Angiotensin-converting enzyme 2	clinvar
AOPEP	HGNC:1361	ENSG00000148120	Q8N6M6	Aminopeptidase O	clinvar
CDK10	HGNC:1770	ENSG00000185324	Q15131	Cyclin-dependent kinase 10	clinvar
DORIP1	HGNC:19834	ENSG00000179476	Q4W4Y0	Dopamine receptor-interacting protein 1	clinvar
ANKRD11	HGNC:21316	ENSG00000167522	Q6UB99	Ankyrin repeat domain-containing protein 11	clinvar
BRK1	HGNC:23057	ENSG00000254999	Q8WUW1	Protein BRICK1	clinvar
ZNF276	HGNC:23330	ENSG00000158805	Q8N554	Zinc finger protein 276	clinvar
ACSF3	HGNC:27288	ENSG00000176715	Q4G176	Malonate–CoA ligase ACSF3, mitochondrial	clinvar
CENPBD1P	HGNC:28272	ENSG00000177946	B2RD01	Putative CENPB DNA-binding domain-containing protein 1	clinvar
FANCD2OS	HGNC:28623	ENSG00000163705	Q96PS1	FANCD2 opposite strand protein	clinvar
SPIRE2	HGNC:30623	ENSG00000204991	Q8WWL2	Protein spire homolog 2	clinvar
POLG	HGNC:9179	ENSG00000140521	P54098	DNA polymerase subunit gamma-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BRCA2	Breast cancer type 2 susceptibility protein	Involved in double-strand break repair and/or homologous recombination.
BRIP1	Fanconi anemia group J protein	DNA-dependent ATPase and 5’-3’ DNA helicase required for the maintenance of chromosomal stability.
FANCL	E3 ubiquitin-protein ligase FANCL	Ubiquitin ligase protein that mediates monoubiquitination of FANCD2 in the presence of UBE2T, a key step in the DNA damage pathway.
FANCM	Fanconi anemia group M protein	DNA-dependent ATPase component of the Fanconi anemia (FA) core complex.
SLX4	Structure-specific endonuclease subunit SLX4	Regulatory subunit that interacts with and increases the activity of different structure-specific endonucleases.
RFWD3	E3 ubiquitin-protein ligase RFWD3	E3 ubiquitin-protein ligase required for the repair of DNA interstrand cross-links (ICL) in response to DNA damage.
FANCI	Fanconi anemia group I protein	Plays an essential role in the repair of DNA double-strand breaks by homologous recombination and in the repair of interstrand DNA cross-links (ICLs) by promoting FANCD2 monoubiquitination by FANCL and participating in recruitment to DNA r…
PALB2	Partner and localizer of BRCA2	Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks.
FANCA	Fanconi anemia group A protein	DNA repair protein that may operate in a postreplication repair or a cell cycle checkpoint function.
FANCB	Fanconi anemia group B protein	DNA repair protein required for FANCD2 ubiquitination.
FANCC	Fanconi anemia group C protein	DNA repair protein that may operate in a postreplication repair or a cell cycle checkpoint function.
FANCD2	Fanconi anemia group D2 protein	Required for maintenance of chromosomal stability.
FANCE	Fanconi anemia group E protein	As part of the Fanconi anemia (FA) complex functions in DNA cross-links repair.
FANCF	Fanconi anemia group F protein	DNA repair protein that may operate in a postreplication repair or a cell cycle checkpoint function.
FANCG	Fanconi anemia group G protein	DNA repair protein that may operate in a postreplication repair or a cell cycle checkpoint function.
BRCA1	Breast cancer type 1 susceptibility protein	E3 ubiquitin-protein ligase that specifically mediates the formation of ‘Lys-6’-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage.
XRCC2	DNA repair protein XRCC2	Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA, thought to repair chromosomal fragmentation, translocations and deletions.
UBE2T	Ubiquitin-conjugating enzyme E2 T	Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins.
ERCC4	DNA repair endonuclease XPF	Catalytic component of a structure-specific DNA repair endonuclease responsible for the 5-prime incision during DNA repair, and which is essential for nucleotide excision repair (NER) and interstrand cross-link (ICL) repair.
MAD2L2	Mitotic spindle assembly checkpoint protein MAD2B	Adapter protein able to interact with different proteins and involved in different biological processes.
RAD51	DNA repair protein RAD51 homolog 1	Plays an important role in homologous strand exchange, a key step in DNA repair through homologous recombination (HR).
RAD51C	DNA repair protein RAD51 homolog 3	Essential for the homologous recombination (HR) pathway of DNA repair.
VCP	Transitional endoplasmic reticulum ATPase	Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis.
VRK2	Serine/threonine-protein kinase VRK2	Serine/threonine kinase that regulates several signal transduction pathways.
ACE2	Angiotensin-converting enzyme 2	Essential counter-regulatory carboxypeptidase of the renin-angiotensin hormone system that is a critical regulator of blood volume, systemic vascular resistance, and thus cardiovascular homeostasis.
AOPEP	Aminopeptidase O	Aminopeptidase which catalyzes the hydrolysis of amino acid residues from the N-terminus of peptide or protein substrates.
CDK10	Cyclin-dependent kinase 10	Cyclin-dependent kinase that phosphorylates the transcription factor ETS2 (in vitro) and positively controls its proteasomal degradation (in cells).
DORIP1	Dopamine receptor-interacting protein 1	Could be a regulator of the dopamine receptor signaling pathway.
ANKRD11	Ankyrin repeat domain-containing protein 11	Chromatin regulator which modulates histone acetylation and gene expression in neural precursor cells.
BRK1	Protein BRICK1	Involved in regulation of actin and microtubule organization.
ZNF276	Zinc finger protein 276	May be involved in transcriptional regulation.
ACSF3	Malonate–CoA ligase ACSF3, mitochondrial	Catalyzes the initial reaction in intramitochondrial fatty acid synthesis, by activating malonate and methylmalonate, but not acetate, into their respective CoA thioester.
FANCD2OS	FANCD2 opposite strand protein	Reduces testosterone levels by inhibiting steroidogenic enzymes and by promoting apoptosis in Leydig cells.
SPIRE2	Protein spire homolog 2	Acts as an actin nucleation factor, remains associated with the slow-growing pointed end of the new filament.
POLG	DNA polymerase subunit gamma-1	Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).

Protein-family classification

Druggable: 7 · Difficult: 9 · Unknown: 21 · Druggable fraction: 0.19

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
Protease	2	2.0×	0.639
Transcription factor	7	1.6×	0.639
Kinase	2	1.5×	0.639
Other/Unknown	21	1.0×	0.639
Enzyme (other)	3	1.0×	0.639
Scaffold/PPI	2	0.9×	0.639

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BRCA2	Other/Unknown	no		BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
BRIP1	Enzyme (other)	yes	3.6.4.12	Helicase-like_DEXD_c2, ATP-dep_Helicase_C, RAD3-like_helicase_DEAD
FANCL	Transcription factor	no	2.3.2.27	Znf_RING/FYVE/PHD, UBQ-conjugating_enzyme/RWD, FancL_WD-rpt_cont_dom
FANCM	Other/Unknown	no		Helicase_C-like, ERCC4_domain, RuvA_2-like
SLX4	Other/Unknown	no		BTB/POZ_dom, Rad18_UBZ4, SKP1/BTB/POZ_sf
RFWD3	Transcription factor	no		WD40_rpt, Znf_RING, Znf_RING/FYVE/PHD
FANCI	Other/Unknown	no		FANCI, FANCI_S1-cap, FANCI_S1
PALB2	Scaffold/PPI	no		WD40/YVTN_repeat-like_dom_sf, PALB2_WD40, WD40_repeat_dom_sf
FANCA	Other/Unknown	no		FANCA, Fanconi_A_N, Fanconi_A_C
FANCB	Other/Unknown	no		FANCB
FANCC	Other/Unknown	no		FANCC
FANCD2	Other/Unknown	no		FANCD2
FANCE	Other/Unknown	no		Fanconi_anaemia_gr_E_prot_C, FANCE
FANCF	Other/Unknown	no		FANCF, FANCF_C_sf
FANCG	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, FANCG
BRCA1	Transcription factor	no	2.3.2.27	BRCT_dom, Znf_RING, BRCA1
XRCC2	Other/Unknown	no		Rad51_C, RecA_ATP-bd, P-loop_NTPase
UBE2T	Enzyme (other)	yes	2.3.2.23	UBC, UBQ-conjugating_enzyme/RWD, UBQ-conjugating_AS
ERCC4	Other/Unknown	no		ERCC4_domain, XPF, RuvA_2-like
MAD2L2	Other/Unknown	no		HORMA_dom, HORMA_dom_sf, Mad2-like
RAD51	Transcription factor	no	3.6.4.B7	AAA+_ATPase, DNA_repair_Rad51/TF_NusA_a-hlx, DNA_recomb/repair_Rad51
RAD51C	Other/Unknown	no		Rad51_C, DNA_recomb/repair_RecA-like, RecA_ATP-bd
VCP	Enzyme (other)	yes	3.6.4.6	CDC4_N-term_subdom, AAA+_ATPase, ATPase_AAA_core
VRK2	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
VPS9D1	Other/Unknown	no		VPS9, VPS9_dom_sf, Vps9-like
ACE2	Protease	yes	3.4.15.1	Peptidase_M2, Collectrin_dom
AOPEP	Protease	yes		Peptidase_M1_dom, Peptidase_M1_C, ARM-type_fold
CDK10	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
DORIP1	Other/Unknown	no		C14orf28-like
ANKRD11	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, ANKRD11
BRK1	Other/Unknown	no		BRICK1
ZNF276	Transcription factor	no		Znf_AD, Znf_C2H2_type, Znf_C2H2_sf
ACSF3	Other/Unknown	no		AMP-dep_synth/lig_dom, AMP-binding_CS, AMP-bd_C
CENPBD1P	Transcription factor	no		HTH_CenpB_DNA-bd_dom, HTH_Psq, Homeodomain-like_sf
FANCD2OS	Other/Unknown	no		FANCD2OS
SPIRE2	Transcription factor	no		Znf_FYVE_PHD, KIND_dom, Spire
POLG	Other/Unknown	no		DNA-dir_DNA_pol_A_palm_dom, DNA-dir_DNA_pol_A_mt, RNaseH-like_sf

Expression context

Cohort genes with no expression data: 0.

33 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)	37
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	11
ventricular zone	9
secondary oocyte	8
primordial germ cell in gonad	6
oocyte	5
right hemisphere of cerebellum	5
buccal mucosa cell	5
sperm	4
pancreatic ductal cell	4
left testis	3
right testis	3
ganglionic eminence	3
granulocyte	3
calcaneal tendon	2
tendon of biceps brachii	2
adrenal tissue	2
stromal cell of endometrium	2
ileal mucosa	2
sural nerve	2
mucosa of transverse colon	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BRCA2	184	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone
BRIP1	181	ubiquitous	marker	ventricular zone, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
FANCL	293	ubiquitous	marker	pituitary gland, adenohypophysis, calcaneal tendon
FANCM	203	ubiquitous	marker	sperm, oocyte, male germ line stem cell (sensu Vertebrata) in testis
SLX4	175	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
RFWD3	216	ubiquitous	marker	oocyte, secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis
FANCI	221	ubiquitous	marker	ventricular zone, secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis
PALB2	232	ubiquitous	yes	secondary oocyte, buccal mucosa cell, oocyte
FANCA	185	ubiquitous	marker	right testis, ventricular zone, left testis
FANCB	160	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, buccal mucosa cell
FANCC	195	ubiquitous	marker	pancreatic ductal cell, right lobe of liver, male germ line stem cell (sensu Vertebrata) in testis
FANCD2	200	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, ventricular zone, secondary oocyte
FANCE	184	ubiquitous	marker	buccal mucosa cell, oocyte, secondary oocyte
FANCF	234	ubiquitous	yes	secondary oocyte, endothelial cell, bronchial epithelial cell
FANCG	242	ubiquitous	marker	ventricular zone, ganglionic eminence, right hemisphere of cerebellum
BRCA1	208	ubiquitous	marker	ventricular zone, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
XRCC2	283	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, lateral globus pallidus
UBE2T	220	ubiquitous	marker	oocyte, ventricular zone, ganglionic eminence
ERCC4	242	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue, sperm
MAD2L2	229	ubiquitous	marker	embryo, ganglionic eminence, left testis
RAD51	193	ubiquitous	marker	primordial germ cell in gonad, buccal mucosa cell, ventricular zone
RAD51C	281	ubiquitous	marker	primordial germ cell in gonad, right testis, male germ line stem cell (sensu Vertebrata) in testis
VCP	294	ubiquitous	marker	stromal cell of endometrium, adrenal tissue, islet of Langerhans
VRK2	280	ubiquitous	marker	monocyte, mononuclear cell, calcaneal tendon
VPS9D1	211	ubiquitous	marker	right frontal lobe, right hemisphere of cerebellum, lower esophagus mucosa
ACE2	152	tissue_specific	marker	ileal mucosa, ileum, gall bladder
AOPEP	224	ubiquitous	marker	apex of heart, right coronary artery, ascending aorta
CDK10	286	ubiquitous	marker	right uterine tube, right lobe of thyroid gland, left lobe of thyroid gland
DORIP1	255	ubiquitous	yes	sperm, secondary oocyte, pancreatic ductal cell
ANKRD11	278	ubiquitous	marker	tendon of biceps brachii, sural nerve, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 138.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VCP	10,015
BRCA1	9,064
RAD51	6,465
ACE2	5,940
PALB2	5,641
BRCA2	4,839
FANCD2	3,820
UBE2T	3,706
POLG	3,400
RAD51C	3,396

Intra-cohort edges

A	B	Sources
BRCA1	BRCA2	string_interaction
BRCA1	BRIP1	biogrid_interaction, intact, string_interaction
BRCA1	FANCA	intact, string_interaction
BRCA1	FANCD2	string_interaction
BRCA1	FANCE	intact, string_interaction
BRCA1	FANCF	intact
BRCA1	FANCI	string_interaction
BRCA1	PALB2	biogrid_interaction, intact, string_interaction
BRCA1	RAD51	biogrid_interaction, string_interaction
BRCA1	RAD51C	string_interaction
BRCA1	UBE2T	string_interaction
BRCA1	XRCC2	string_interaction
BRCA2	BRIP1	string_interaction
BRCA2	FANCB	string_interaction
BRCA2	FANCC	string_interaction
BRCA2	FANCD2	intact, string_interaction
BRCA2	FANCE	string_interaction
BRCA2	FANCF	string_interaction
BRCA2	FANCG	string_interaction
BRCA2	FANCI	string_interaction
BRCA2	PALB2	biogrid_interaction, intact, string_interaction
BRCA2	RAD51	biogrid_interaction, intact, string_interaction
BRCA2	RAD51C	biogrid_interaction, string_interaction
BRCA2	XRCC2	string_interaction
BRIP1	FANCA	string_interaction
BRIP1	FANCB	string_interaction
BRIP1	FANCC	string_interaction
BRIP1	FANCD2	string_interaction
BRIP1	FANCE	string_interaction
BRIP1	FANCF	string_interaction
BRIP1	FANCG	string_interaction
BRIP1	FANCI	string_interaction
BRIP1	FANCL	string_interaction
BRIP1	FANCM	string_interaction
BRIP1	PALB2	string_interaction
BRIP1	RFWD3	string_interaction
CDK10	FANCA	string_interaction
CDK10	ZNF276	string_interaction
CENPBD1P	ZNF276	string_interaction
ERCC4	FANCD2	string_interaction
ERCC4	RFWD3	string_interaction
ERCC4	SLX4	biogrid_interaction, intact, string_interaction
FANCA	FANCB	biogrid_interaction, intact, string_interaction
FANCA	FANCC	biogrid_interaction, intact, string_interaction
FANCA	FANCD2	string_interaction
FANCA	FANCE	biogrid_interaction, string_interaction
FANCA	FANCF	biogrid_interaction, intact, string_interaction
FANCA	FANCG	biogrid_interaction, intact, string_interaction
FANCA	FANCI	string_interaction
FANCA	FANCL	biogrid_interaction, intact, string_interaction

Structural data

PDB: 28 · AlphaFold-only: 9 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACE2	Q9BYF1	345
VCP	P55072	144
RAD51	Q06609	52
POLG	P54098	36
BRCA1	P38398	33
MAD2L2	Q9UI95	24
RAD51C	O43502	17
XRCC2	O43543	16
BRCA2	P51587	14
FANCD2	Q9BXW9	13
UBE2T	Q9NPD8	13
ERCC4	Q92889	13
FANCL	Q9NW38	8
FANCI	Q9NVI1	8
FANCM	Q8IYD8	7
SLX4	Q8IY92	7
FANCE	Q9HB96	7
FANCF	Q9NPI8	7
FANCA	O15360	6
FANCB	Q8NB91	6
FANCC	Q00597	6
FANCG	O15287	6
VRK2	Q86Y07	5
BRK1	Q8WUW1	5
PALB2	Q86YC2	4
BRIP1	Q9BX63	3
RFWD3	Q6PCD5	1
SPIRE2	Q8WWL2	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACSF3	Q4G176	86.58
CDK10	Q15131	86.27
AOPEP	Q8N6M6	83.36
DORIP1	Q4W4Y0	83.15
VPS9D1	Q9Y2B5	76.34
CENPBD1P	B2RD01	64.19
FANCD2OS	Q96PS1	61.31
ZNF276	Q8N554	56.21
ANKRD11	Q6UB99	39.44

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 148. Enrichment computed across 37 evidence-associated genes (27 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 27 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Fanconi Anemia Pathway	13	134.1×	6e-24	FANCL, FANCM, SLX4, FANCI, FANCA, FANCB, FANCC, FANCD2 (+5 more)
Resolution of D-loop Structures through Holliday Junction Intermediates	8	89.0×	1e-12	BRCA2, BRIP1, SLX4, PALB2, BRCA1, XRCC2, RAD51, RAD51C
Impaired BRCA2 binding to PALB2	7	118.4×	4e-12	BRCA2, BRIP1, PALB2, BRCA1, XRCC2, RAD51, RAD51C
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	7	109.7×	4e-12	BRCA2, BRIP1, PALB2, BRCA1, XRCC2, RAD51, RAD51C
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	7	109.7×	4e-12	BRCA2, BRIP1, PALB2, BRCA1, XRCC2, RAD51, RAD51C
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	7	109.7×	4e-12	BRCA2, BRIP1, PALB2, BRCA1, XRCC2, RAD51, RAD51C
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	7	102.1×	6e-12	BRCA2, BRIP1, PALB2, BRCA1, XRCC2, RAD51, RAD51C
Homologous DNA Pairing and Strand Exchange	7	98.7×	6e-12	BRCA2, BRIP1, PALB2, BRCA1, XRCC2, RAD51, RAD51C
HDR through Homologous Recombination (HRR)	8	56.4×	1e-11	BRCA2, BRIP1, SLX4, PALB2, BRCA1, XRCC2, RAD51, RAD51C
PKR-mediated signaling	8	41.8×	1e-10	FANCL, FANCM, FANCA, FANCB, FANCC, FANCE, FANCF, FANCG
Presynaptic phase of homologous DNA pairing and strand exchange	6	60.4×	6e-09	BRCA2, BRIP1, BRCA1, XRCC2, RAD51, RAD51C
Impaired BRCA2 binding to RAD51	4	45.7×	2e-05	BRCA2, BRIP1, BRCA1, RAD51
HDR through Single Strand Annealing (SSA)	4	43.4×	2e-05	BRIP1, BRCA1, ERCC4, RAD51
DNA Repair	5	18.2×	7e-05	BRCA2, SLX4, BRCA1, VCP, MAD2L2
Resolution of D-Loop Structures	3	70.5×	9e-05	BRCA2, SLX4, BRCA1
TP53 Regulates Transcription of DNA Repair Genes	4	26.9×	1e-04	FANCI, FANCC, FANCD2, BRCA1
Attachment and Entry	2	211.5×	3e-04	VCP, ACE2
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	2	169.2×	4e-04	VCP, MAD2L2
DNA Damage Bypass	2	169.2×	4e-04	VCP, MAD2L2
Meiotic recombination	4	19.2×	4e-04	BRCA2, BRCA1, RAD51, RAD51C
Homology Directed Repair	3	34.3×	6e-04	BRCA2, SLX4, BRCA1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	3	34.3×	6e-04	BRCA2, SLX4, BRCA1
DNA Double-Strand Break Repair	3	27.6×	0.001	BRCA2, SLX4, BRCA1
Early SARS-CoV-2 Infection Events	2	76.9×	0.002	VCP, ACE2
Defective homologous recombination repair (HRR) due to PALB2 loss of function	2	70.5×	0.002	BRCA2, BRCA1
Diseases of DNA Double-Strand Break Repair	2	60.4×	0.003	BRCA2, BRCA1
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	2	60.4×	0.003	BRCA2, BRCA1
Attachment and Entry	2	44.5×	0.005	VCP, ACE2
Diseases of DNA repair	2	42.3×	0.005	BRCA2, BRCA1
KEAP1-NFE2L2 pathway	3	13.4×	0.007	PALB2, BRCA1, VCP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 36 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
interstrand cross-link repair	13	156.0×	4e-24	FANCL, FANCM, RFWD3, FANCI, FANCA, FANCB, FANCC, FANCD2 (+5 more)
DNA repair	14	24.8×	2e-14	BRIP1, FANCL, SLX4, FANCA, FANCC, FANCG, BRCA1, VCP (+6 more)
double-strand break repair via homologous recombination	9	39.0×	1e-10	BRCA2, SLX4, RFWD3, PALB2, BRCA1, XRCC2, ERCC4, RAD51 (+1 more)
DNA damage response	9	13.4×	1e-06	FANCL, RFWD3, FANCF, FANCG, BRCA1, VCP, VRK2, UBE2T (+1 more)
regulation of DNA damage checkpoint	4	124.8×	1e-06	BRCA2, RFWD3, BRCA1, RAD51
nucleotide-excision repair	5	53.2×	2e-06	BRCA2, BRIP1, SLX4, FANCC, ERCC4
double-strand break repair	5	28.2×	4e-05	BRCA2, BRIP1, BRCA1, VCP, MAD2L2
telomere maintenance via recombination	3	127.7×	5e-05	BRCA2, RAD51, RAD51C
double-strand break repair involved in meiotic recombination	3	108.0×	8e-05	BRIP1, FANCD2, RAD51
mitotic recombination-dependent replication fork processing	2	468.1×	1e-04	BRCA2, RAD51
resolution of meiotic recombination intermediates	3	78.0×	2e-04	FANCM, SLX4, ERCC4
response to X-ray	3	73.9×	2e-04	BRCA2, XRCC2, RAD51
DNA strand invasion	2	234.1×	6e-04	XRCC2, RAD51
regulation of CD40 signaling pathway	2	234.1×	6e-04	FANCA, FANCD2
response to gamma radiation	3	48.4×	6e-04	BRCA2, FANCD2, XRCC2
replication-born double-strand break repair via sister chromatid exchange	2	156.0×	0.001	FANCB, RAD51
replication fork processing	3	35.1×	0.001	FANCM, RFWD3, RAD51
cellular response to ionizing radiation	3	34.2×	0.001	BRCA2, BRCA1, RAD51
regulation of regulatory T cell differentiation	2	104.0×	0.002	FANCA, FANCD2
protein-DNA covalent cross-linking repair	2	93.6×	0.003	BRIP1, VCP
homologous recombination	2	78.0×	0.004	BRIP1, BRCA1
negative regulation of telomere maintenance via telomere lengthening	2	78.0×	0.004	SLX4, ERCC4
inner cell mass cell proliferation	2	55.1×	0.007	BRCA2, PALB2
protein K6-linked ubiquitination	2	55.1×	0.007	BRCA1, UBE2T
translesion synthesis	2	52.0×	0.008	VCP, MAD2L2
gamete generation	2	49.3×	0.008	FANCL, FANCD2
female gonad development	2	44.6×	0.010	BRCA2, FANCA
regulation of inflammatory response	3	14.0×	0.013	FANCA, FANCD2, ACE2
negative regulation of double-strand break repair via homologous recombination	2	34.7×	0.015	FANCB, MAD2L2
cellular response to oxidative stress	3	12.9×	0.016	FANCC, FANCD2, VRK2

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Busulfan, Eltrombopag, Filgrastim, Fludarabine, Fludarabine Phosphate, Methylprednisolone, Mycophenolate Mofetil, Plerixafor, Sirolimus.

Drug target analysis

Approved (phase 4): 6 · Phase ≥3: 6 · Phased (≥1): 7 · Undrugged: 30

Druggability breadth: 16 of 37 evidence-associated genes (43%) 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
BRCA1	RIBOFLAVIN
UBE2T	ZINC CHLORIDE
VCP	CLOTRIMAZOLE
VRK2	RUXOLITINIB
ACE2	CAPTOPRIL
POLG	ADEFOVIR DIPIVOXIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BRCA1	12	4
ACE2	8	4
VCP	4	4
VRK2	4	4
CDK10	3	2
UBE2T	1	4
POLG	1	4
BRCA2	0	0
BRIP1	0	0
FANCL	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
RIBOFLAVIN	4	BRCA1
DAUNORUBICIN HYDROCHLORIDE	4	BRCA1
TOPOTECAN HYDROCHLORIDE	4	BRCA1
DAUNORUBICIN	4	BRCA1
DOXORUBICIN HYDROCHLORIDE	4	BRCA1
MESALAMINE	4	BRCA1
DIPYRIDAMOLE	4	BRCA1
ZINC CHLORIDE	4	UBE2T
CLOTRIMAZOLE	4	VCP
GANCICLOVIR	4	VCP
HEXACHLOROPHENE	4	VCP
RUXOLITINIB	4	VRK2
BOSUTINIB	4	VRK2
DASATINIB	4	VRK2
CAPTOPRIL	4	ACE2
FLUORESCEIN	4	ACE2
CINACALCET	4	ACE2
HYDROXYCHLOROQUINE	4	ACE2
CHLOROQUINE	4	ACE2
ADEFOVIR DIPIVOXIL	4	POLG
CURCUMIN	3	BRCA1
SURAMIN	3	BRCA1
SURAMIN HEXASODIUM	3	BRCA1
ALVOCIDIB	3	VRK2
SODIUM TANSHINONE IIA SULFONATE	2	BRCA1
HOMIDIUM BROMIDE	2	BRCA1
DIMINAZENE	2	ACE2
CEPHARANTHINE	2	ACE2
MOLIBRESIB	2	CDK10
AT-9283	2	CDK10

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 8.

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

Symbol	Assays	Type breakdown
VRK2	146	Binding:146
RAD51	124	Binding:116, ADMET:8
VCP	120	Binding:120
ACE2	107	Binding:98, Functional:6, ADMET:3
CDK10	59	Binding:59
POLG	33	Binding:30, ADMET:2, Functional:1
ERCC4	28	Binding:28
UBE2T	15	Binding:15
BRCA1	13	Binding:9, Functional:4
FANCF	7	Binding:7
FANCD2	2	Binding:2
FANCI	1	Binding:1
MAD2L2	1	Binding:1
AOPEP	1	ADMET:1
BRK1	1	Binding:1
ACSF3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRIP1	3.6.4.12	DNA helicase
FANCL	2.3.2.27	RING-type E3 ubiquitin transferase
BRCA1	2.3.2.27	RING-type E3 ubiquitin transferase
UBE2T	2.3.2.23, 2.3.2.24	E2 ubiquitin-conjugating enzyme, (E3-independent) E2 ubiquitin-conjugating enzyme
RAD51	3.6.4.B7
VCP	3.6.4.6	vesicle-fusing ATPase
ACE2	3.4.15.1, 3.4.17.23	peptidyl-dipeptidase A, angiotensin-converting enzyme 2
CDK10	2.7.11.22	cyclin-dependent kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
RAD51	124
VCP	120
VRK2	146
ACE2	107

Pharmacogenomics

Cohort genes with a PharmGKB record: 36; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
RIBOFLAVIN	4	BRCA1
DAUNORUBICIN HYDROCHLORIDE	4	BRCA1
TOPOTECAN HYDROCHLORIDE	4	BRCA1
DAUNORUBICIN	4	BRCA1
DOXORUBICIN HYDROCHLORIDE	4	BRCA1
MESALAMINE	4	BRCA1
DIPYRIDAMOLE	4	BRCA1
ZINC CHLORIDE	4	UBE2T
CLOTRIMAZOLE	4	VCP
GANCICLOVIR	4	VCP
HEXACHLOROPHENE	4	VCP
RUXOLITINIB	4	VRK2
BOSUTINIB	4	VRK2
DASATINIB	4	VRK2
CAPTOPRIL	4	ACE2
FLUORESCEIN	4	ACE2
CINACALCET	4	ACE2
HYDROXYCHLOROQUINE	4	ACE2
CHLOROQUINE	4	ACE2
ADEFOVIR DIPIVOXIL	4	POLG
CURCUMIN	3	BRCA1
SURAMIN	3	BRCA1
SURAMIN HEXASODIUM	3	BRCA1
ALVOCIDIB	3	VRK2
SODIUM TANSHINONE IIA SULFONATE	2	BRCA1
HOMIDIUM BROMIDE	2	BRCA1
DIMINAZENE	2	ACE2
CEPHARANTHINE	2	ACE2
MOLIBRESIB	2	CDK10
AT-9283	2	CDK10

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	6	BRCA1, UBE2T, VCP, VRK2, ACE2, POLG
B	Phased (≥1) drug, not yet approved	1	CDK10
C	Druggable family + PDB, no drug	1	BRIP1
D	Druggable family + AlphaFold only, no drug	1	AOPEP
E	Difficult family or no structure, no drug	28	BRCA2, FANCL, FANCM, SLX4, RFWD3, FANCI, PALB2, FANCA, FANCB, FANCC (+18 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RAD51	124	BRCA1
BRCA2	0	BRCA1
BRIP1	0	BRCA1
PALB2	0	BRCA1
FANCD2	2	BRCA1
ZNF276	0	CDK10
FANCL	0	—
FANCM	0	—
SLX4	0	—
RFWD3	0	—
FANCI	1	—
FANCA	0	—
FANCB	0	—
FANCC	0	—
FANCE	0	—
FANCF	7	—
FANCG	0	—
XRCC2	0	—
ERCC4	28	—
MAD2L2	1	—
RAD51C	0	—
VPS9D1	0	—
AOPEP	1	—
DORIP1	0	—
ANKRD11	0	—
BRK1	1	—
ACSF3	1	—
CENPBD1P	0	—
FANCD2OS	0	—
SPIRE2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 84.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	37
PHASE2	17
PHASE1/PHASE2	15
PHASE1	11
PHASE2/PHASE3	2
PHASE3	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00352976	PHASE2/PHASE3	COMPLETED	TBI Dose De-escalation for Fanconi Anemia
NCT01019876	PHASE2/PHASE3	COMPLETED	Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases
NCT06519786	PHASE3	UNKNOWN	Safety and Efficacy of Metformin for Treatment of Cytopenia in Children and Adolescents With Fanconi Anemia
NCT02143830	PHASE2	RECRUITING	HSCT for Patients With Fanconi Anemia Using Risk-Adjusted Chemotherapy
NCT03206086	PHASE2	ACTIVE_NOT_RECRUITING	Eltrombopag for People With Fanconi Anemia
NCT03579875	PHASE2	RECRUITING	Alpha/Beta TCD HCT in Patients With Inherited BMF Disorders
NCT04232085	PHASE2	RECRUITING	Regenerative Medicine to Restore Hematopoiesis and Immune Function in Immunodeficiencies and Inherited Bone Marrow Failures
NCT04784052	PHASE1/PHASE2	RECRUITING	Depleted Donor Stem Cell Transplant in Children and Adults With Fanconi Anemia After Being Conditioned With a Regimen Containing Briquilimab
NCT06648096	PHASE1/PHASE2	RECRUITING	Afatinib in Patients With Fanconi Anemia (FA) and Advanced Head and Neck Squamous Cell Carcinoma (HNSCC)
NCT07408583	PHASE1/PHASE2	NOT_YET_RECRUITING	Prenatal Transplantation for Fetuses With Fanconi Anemia
NCT00000603	PHASE2	COMPLETED	Cord Blood Stem Cell Transplantation Study (COBLT)
NCT00001749	PHASE2	COMPLETED	Medical Treatment for Diamond Blackfan Anemia
NCT00004787	PHASE2	COMPLETED	Phase II Pilot Study of Granulocyte Colony-Stimulating Factor for Inherited Bone Marrow Failure Syndromes
NCT00005898	PHASE1/PHASE2	COMPLETED	Phase I/II Study of Total Body Irradiation, Cyclophosphamide, and Fludarabine Followed by Alternate Donor Hematopoietic Cell Transplantation in Patients With Fanconi’s Anemia
NCT00053989	PHASE2	COMPLETED	NMA Allogeneic Hematopoietic Cell Transplant in Hematologic Cancer/Disorders
NCT00084695	PHASE2	UNKNOWN	Umbilical Cord Blood for Stem Cell Transplantation in Treating Young Patients With Malignant or Nonmalignant Diseases
NCT00167206	PHASE1/PHASE2	TERMINATED	Stem Cell Transplantation for Fanconi Anemia
NCT00258427	PHASE2	COMPLETED	Hematopoietic Stem Cell Transplantation in High Risk Patients With Fanconi Anemia
NCT00305708	PHASE1/PHASE2	COMPLETED	Busulfan, Antithymocyte Globulin, and Fludarabine Followed By a Donor Stem Cell Transplant in Treating Young Patients With Blood Disorders, Bone Marrow Disorders, Chronic Myelogenous Leukemia in First Chronic Phase, or Acute Myeloid Leukemia in First Remission
NCT00453388	PHASE2	COMPLETED	Fludarabine Phosphate, Cyclophosphamide, and Total-Body Irradiation Followed by Donor Bone Marrow Transplant, Mycophenolate Mofetil, and Cyclosporine in Treating Patients With Fanconi Anemia
NCT00479115	PHASE1/PHASE2	COMPLETED	Mobilization and Collection of Peripheral Blood Stem Cells in Patients With Fanconi Anemia Using G-CSF and AMD3100
NCT00590460	PHASE1/PHASE2	TERMINATED	Antibody Conditioning Regimen For Allogeneic Donor Stem Cell Transplantation Of Patients With Fanconi Anemia
NCT00630253	PHASE1/PHASE2	COMPLETED	Cytoxan, Fludara, and Antithymocyte Globulin Conditioning Followed By Stem Cell Transplant in Treating Fanconi Anemia
NCT01001598	PHASE1/PHASE2	TERMINATED	Safety and Efficacy Trial of Danazol in Patients With Fanconi Anemia or Dyskeratosis Congenita
NCT01071239	PHASE2	COMPLETED	Hematopoietic Stem Cell Transplant for Fanconi Anemia
NCT02065869	PHASE1/PHASE2	TERMINATED	Safety Study of Gene Modified Donor T-cells Following TCRαβ+ Depleted Stem Cell Transplant
NCT02678533	PHASE1/PHASE2	COMPLETED	Mobilization and Collection of Peripheral Blood Stem Cells in Patients With Fanconi Anemia Using G-CSF and Plerixafor
NCT02931071	PHASE2	COMPLETED	Clinical Phase II Trial to Evaluate CD34+ Cells Mobilization and Collection in Patients With Fanconi Anemia for Subsequent Transduction With a Lentiviral Vector Carring FANCA Gene. FANCOSTEM-1
NCT03157804	PHASE1/PHASE2	COMPLETED	Lentiviral-mediated Gene Therapy of Fanconi Anemia Patients Subtype A
NCT03398824	PHASE2	COMPLETED	Pilot Study of Metformin for Patients With Fanconi Anemia
NCT03476330	PHASE2	COMPLETED	Quercetin Chemoprevention for Squamous Cell Carcinoma in Patients With Fanconi Anemia
NCT03600909	PHASE2	TERMINATED	A Study of the Effect of Blood Stem Cell Transplant After Chemotherapy Alone in Patients With Fanconi Anemia
NCT03733249	PHASE1/PHASE2	TERMINATED	Long Term Follow-up Study for Patients Enrolled on the BP-004 Clinical Study
NCT04522375	PHASE1/PHASE2	WITHDRAWN	A Dose Escalation Study of FP-045 in Patients With Fanconi Anemia
NCT06045052	PHASE2	COMPLETED	Eltrombopag for Treatment of Fanconi Anemia
NCT00001399	PHASE1	COMPLETED	Gene Therapy for the Treatment of Fanconi’s Anemia Type C
NCT00005896	PHASE1	UNKNOWN	Phase I Pilot Study of CD34 Enriched, Fanconi’s Anemia Complementation Group C Gene Transduced Autologous Peripheral Blood Stem Cell Transplantation in Patients With Fanconi’s Anemia
NCT00006127	PHASE1	UNKNOWN	Phase I Study of Amifostine in Patients With Bone Marrow Failure Related to Fanconi’s Anemia
NCT00093743	PHASE1	COMPLETED	Low-Dose Total-Body Irradiation and Fludarabine Phosphate Followed by Unrelated Donor Stem Cell Transplant in Treating Patients With Fanconi Anemia
NCT00243399	PHASE1	COMPLETED	Oxandrolone for the Treatment of Bone Marrow Aplasia in Fanconi Anemia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLUDARABINE PHOSPHATE	4	23
PLERIXAFOR	4	9
ALEFACEPT	4	1
ALEMTUZUMAB	4	1
AMIFOSTINE	4	1
BUSULFAN	4	1
DANAZOL	4	1
ELTROMBOPAG	4	1
METFORMIN	4	1
OXANDROLONE	4	1
SIROLIMUS	4	1
FLUDARABINE	3	2
RIMIDUCID	2	2
ANTILYMPHOCYTE IMMUNOGLOBULIN (HORSE)	2	1
BRIQUILIMAB	2	1
MOZAFANCOGENE AUTOTEMCEL	2	1
RIVOGENLECLEUCEL	2	1
CHEMBL290077	0	2
CHEMBL2347958	0	1
CHEMBL4283673	0	1
CHEMBL4759112	0	1

Cohort genes: BRCA2, BRIP1, FANCL, FANCM, SLX4, RFWD3, FANCI, PALB2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, BRCA1, XRCC2, UBE2T, ERCC4, MAD2L2, RAD51, RAD51C, VCP, VRK2, VPS9D1, ACE2, AOPEP, CDK10, DORIP1, ANKRD11, BRK1, ZNF276, ACSF3, FANCD2OS, SPIRE2, POLG
Drugs: Fludarabine Phosphate, Plerixafor, Alefacept, Alemtuzumab, Amifostine, Busulfan, Danazol, Eltrombopag, Metformin, Oxandrolone, Sirolimus, Fludarabine