FANCD2

Summary

FANCD2 (FA complementation group D2, HGNC:3585) is a protein-coding gene on chromosome 3p25.3, encoding Fanconi anemia group D2 protein (Q9BXW9). Required for maintenance of chromosomal stability. It is a selective cancer dependency (DepMap: 13.3% of cell lines).

The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group D2. This protein is monoubiquinated in response to DNA damage, resulting in its localization to nuclear foci with other proteins (BRCA1 AND BRCA2) involved in homology-directed DNA repair. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 2177 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Fanconi anemia complementation group D2 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 2,110 total — 132 pathogenic, 127 likely-pathogenic (top 1% of genes corpus-wide)
• GTEx eGene: eQTL in 24 tissues, sQTL in 6 (q < 0.05)
• Phenotypes (HPO): 143
• Cancer dependency (DepMap): dependent in 13.3% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.78 (unconstrained)
• MANE Select transcript: NM_001018115
• Interaction hub: 2,210 STRING partners (top 6% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3585
Approved symbol	FANCD2
Name	FA complementation group D2
Location	3p25.3
Locus type	gene with protein product
Status	Approved
Aliases	FAD, FA-D2
Ensembl gene	ENSG00000144554
Ensembl biotype	protein_coding
OMIM	613984
Entrez	2177

Gene structure

Transcript identifiers

Ensembl transcripts: 45 — 30 protein_coding, 6 nonsense_mediated_decay, 5 protein_coding_CDS_not_defined, 4 retained_intron

MANE Select: ENST00000675286

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 3, TSL 4: 2, TSL 5: 2

ENST00000675286, ENST00000287647, ENST00000419585, ENST00000421731, ENST00000431693, ENST00000435522, ENST00000438741, ENST00000464934, ENST00000470028, ENST00000470757, ENST00000480909, ENST00000625535, ENST00000676013, ENST00000681997, ENST00000682647, ENST00000683263, ENST00000683312, ENST00000683933, ENST00000915094, ENST00000915095, ENST00000915096, ENST00000915097, ENST00000915098, ENST00000915099, ENST00000915100, ENST00000915101, ENST00000915102, ENST00000915103, ENST00000915104, ENST00000915105, ENST00000915106, ENST00000915107, ENST00000915108, ENST00000915109, ENST00000915110, ENST00000915111, ENST00000915112, ENST00000915113, ENST00000915114, ENST00000915115, ENST00001011692, ENST00001059487, ENST00001059488, ENST00001059489, ENST00001144855

RefSeq mRNA: 6 — MANE Select: NM_001018115 NM_001018115, NM_001319984, NM_001374253, NM_001374254, NM_001374255, NM_033084

CCDS: CCDS2595, CCDS33696

Canonical transcript exons

ENST00000675286 — 44 exons

Exon	Start	End
ENSE00001029673	10088828	10088950
ENSE00001029677	10081346	10081464
ENSE00001029687	10072871	10072981
ENSE00001029690	10081100	10081228
ENSE00001029694	10078081	10078197
ENSE00001029703	10062151	10062211
ENSE00001029705	10088449	10088542
ENSE00001029707	10085812	10085922
ENSE00001029708	10073253	10073362
ENSE00001029711	10087134	10087264
ENSE00001029716	10090292	10090385
ENSE00001029723	10074530	10074673
ENSE00001077499	10041623	10041710
ENSE00001077506	10034695	10034798
ENSE00001077511	10034469	10034536
ENSE00001164195	10043484	10043592
ENSE00001164200	10043050	10043150
ENSE00001164211	10042559	10042663
ENSE00001218781	10028625	10028721
ENSE00001633006	10052387	10052497
ENSE00001733407	10043829	10043864
ENSE00001735136	10063792	10063911
ENSE00001783284	10064356	10064429
ENSE00001785431	10060294	10060403
ENSE00001785971	10049374	10049505
ENSE00003458996	10039279	10039357
ENSE00003466949	10046580	10046723
ENSE00003513939	10096326	10096472
ENSE00003532627	10032832	10032972
ENSE00003561424	10065394	10065494
ENSE00003568884	10067209	10067317
ENSE00003601643	10064729	10064875
ENSE00003603756	10036287	10036339
ENSE00003622610	10092181	10092252
ENSE00003622867	10098720	10098815
ENSE00003630166	10094289	10094363
ENSE00003649789	10093285	10093323
ENSE00003653588	10095200	10095274
ENSE00003672112	10035173	10035233
ENSE00003678854	10065864	10065979
ENSE00003694275	10047917	10048051
ENSE00003694383	10039721	10039845
ENSE00003900370	10101188	10101932
ENSE00003902164	10026437	10026473

Expression profiles

Bgee: expression breadth ubiquitous, 200 present calls, max score 93.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.4493 / max 208.2075, expressed in 1266 samples.

Highest expression (Bgee): male germ line stem cell (sensu Vertebrata) in testis, ventricular zone, secondary oocyte, testis, oviduct epithelium.

Genetic regulation across tissues (GTEx eQTL / sQTL)

FANCD2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 24 tissues and its splicing (sQTL) in 6 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 30 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells EBV-transformed lymphocytes	sqtl	1.6e-23	-0.97	3:10046275:G:C
Testis	sqtl	7.9e-17	+1.05	3:10045694:C:T
Whole Blood	eqtl	1.5e-11	-0.20	3:10079420:G:T
Skin Not Sun Exposed Suprapubic	eqtl	7.3e-11	-0.30	3:10046275:G:C
Skin Sun Exposed Lower leg	eqtl	2.9e-10	-0.27	3:10046275:G:C
Testis	eqtl	9.5e-10	-0.33	3:10045694:C:T
Nerve Tibial	eqtl	2.4e-09	-0.31	3:10046275:G:C
Adipose Subcutaneous	eqtl	4.9e-08	-0.31	3:10046275:G:C
Adipose Visceral Omentum	eqtl	4.2e-06	-0.28	3:10046275:G:C
Breast Mammary Tissue	eqtl	5.9e-06	-0.25	3:10046275:G:C
Esophagus Muscularis	eqtl	2.0e-05	-0.29	3:10046275:G:C
Lung	eqtl	4.6e-05	-0.16	3:10032657:A:ATTTG
Esophagus Gastroesophageal Junction	eqtl	1.3e-04	-0.35	3:10046275:G:C
Skin Sun Exposed Lower leg	sqtl	2.6e-04	-0.47	3:10046275:G:C
Pituitary	eqtl	7.9e-04	-0.48	3:10046275:G:C
Esophagus Mucosa	eqtl	8.1e-04	-0.39	3:10048460:C:T
Spleen	eqtl	2.2e-03	-0.21	3:10079420:G:T
Colon Transverse	eqtl	2.4e-03	-0.21	3:10050365:T:C
Brain Cortex	eqtl	4.2e-03	-0.40	3:10046275:G:C
Artery Tibial	eqtl	5.8e-03	-0.21	3:10046275:G:C

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
35270	6.8726	1225
35269	0.4414	261
35271	0.1234	60
35268	0.0118	5

Top tissues by expression

showing 100 of 250 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.92	gold quality
ventricular zone	UBERON:0003053	92.99	gold quality
secondary oocyte	CL:0000655	92.84	gold quality
right testis	UBERON:0004534	92.15	gold quality
left testis	UBERON:0004533	91.50	gold quality
testis	UBERON:0000473	90.82	gold quality
oviduct epithelium	UBERON:0004804	90.48	gold quality
ganglionic eminence	UBERON:0004023	89.65	gold quality
oocyte	CL:0000023	89.52	gold quality
bone marrow cell	CL:0002092	86.20	gold quality
buccal mucosa cell	CL:0002336	85.53	gold quality
mucosa of transverse colon	UBERON:0004991	85.33	gold quality
bone marrow	UBERON:0002371	84.97	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.58	gold quality
spleen	UBERON:0002106	84.33	gold quality
lymph node	UBERON:0000029	84.26	gold quality
vermiform appendix	UBERON:0001154	84.02	gold quality
trabecular bone tissue	UBERON:0002483	83.51	gold quality
epithelium of nasopharynx	UBERON:0001951	83.38	gold quality
granulocyte	CL:0000094	83.21	gold quality
lower esophagus mucosa	UBERON:0035834	82.57	gold quality
tonsil	UBERON:0002372	81.42	gold quality
rectum	UBERON:0001052	80.99	gold quality
stromal cell of endometrium	CL:0002255	80.84	gold quality
esophagus mucosa	UBERON:0002469	80.51	gold quality
small intestine Peyer’s patch	UBERON:0003454	80.45	gold quality
esophagus squamous epithelium	UBERON:0006920	80.42	gold quality
pancreatic ductal cell	CL:0002079	80.10	silver quality
right uterine tube	UBERON:0001302	79.97	gold quality
blood	UBERON:0000178	79.41	gold quality
colonic epithelium	UBERON:0000397	78.38	gold quality
small intestine	UBERON:0002108	78.28	gold quality
skin of leg	UBERON:0001511	78.17	gold quality
caecum	UBERON:0001153	78.06	gold quality
skin of abdomen	UBERON:0001416	78.05	gold quality
adrenal tissue	UBERON:0018303	77.93	gold quality
ovary	UBERON:0000992	77.62	gold quality
fallopian tube	UBERON:0003889	77.58	gold quality
gingival epithelium	UBERON:0001949	77.56	gold quality
epithelial cell of pancreas	CL:0000083	77.38	gold quality
sural nerve	UBERON:0015488	77.08	gold quality
left ovary	UBERON:0002119	76.94	gold quality
transverse colon	UBERON:0001157	76.92	gold quality
zone of skin	UBERON:0000014	76.63	gold quality
amniotic fluid	UBERON:0000173	76.54	gold quality
thymus	UBERON:0002370	76.23	gold quality
minor salivary gland	UBERON:0001830	76.11	gold quality
mucosa of stomach	UBERON:0001199	75.81	gold quality
right ovary	UBERON:0002118	75.76	gold quality
esophagus	UBERON:0001043	75.72	gold quality
duodenum	UBERON:0002114	75.48	gold quality
metanephros cortex	UBERON:0010533	75.44	gold quality
left uterine tube	UBERON:0001303	75.18	gold quality
leukocyte	CL:0000738	75.05	gold quality
mouth mucosa	UBERON:0003729	75.02	gold quality
vagina	UBERON:0000996	75.01	gold quality
intestine	UBERON:0000160	74.92	gold quality
endometrium	UBERON:0001295	74.73	gold quality
germinal epithelium of ovary	UBERON:0001304	74.68	gold quality
monocyte	CL:0000576	74.60	gold quality
oral cavity	UBERON:0000167	74.53	gold quality
body of stomach	UBERON:0001161	74.52	gold quality
calcaneal tendon	UBERON:0003701	74.45	gold quality
palpebral conjunctiva	UBERON:0001812	74.40	gold quality
ectocervix	UBERON:0012249	74.11	gold quality
female reproductive system	UBERON:0000474	74.10	gold quality
body of uterus	UBERON:0009853	74.09	gold quality
colon	UBERON:0001155	73.75	gold quality
gingiva	UBERON:0001828	73.71	gold quality
tibial nerve	UBERON:0001323	73.70	gold quality
large intestine	UBERON:0000059	73.63	gold quality
smooth muscle tissue	UBERON:0001135	73.56	gold quality
upper lobe of left lung	UBERON:0008952	73.40	gold quality
placenta	UBERON:0001987	73.22	gold quality
stomach	UBERON:0000945	73.19	gold quality
metanephros	UBERON:0000081	73.13	gold quality
upper lobe of lung	UBERON:0008948	72.94	gold quality
gall bladder	UBERON:0002110	72.88	gold quality
prostate gland	UBERON:0002367	72.81	gold quality
saliva-secreting gland	UBERON:0001044	72.69	gold quality
ileal mucosa	UBERON:0000331	72.49	gold quality
body of pancreas	UBERON:0001150	72.29	gold quality
uterus	UBERON:0000995	72.25	gold quality
right adrenal gland cortex	UBERON:0035827	72.13	gold quality
right lung	UBERON:0002167	72.02	gold quality
subcutaneous adipose tissue	UBERON:0002190	71.96	gold quality
endocervix	UBERON:0000458	71.57	gold quality
tibia	UBERON:0000979	71.42	gold quality
omental fat pad	UBERON:0010414	71.41	gold quality
pancreas	UBERON:0001264	71.40	gold quality
peritoneum	UBERON:0002358	71.39	gold quality
uterine cervix	UBERON:0000002	71.10	gold quality
right adrenal gland	UBERON:0001233	71.09	gold quality
islet of Langerhans	UBERON:0000006	70.86	gold quality
colonic mucosa	UBERON:0000317	70.79	gold quality
adipose tissue of abdominal region	UBERON:0007808	70.79	gold quality
anatomical system	UBERON:0000467	70.76	gold quality
muscle layer of sigmoid colon	UBERON:0035805	70.67	gold quality
lower esophagus	UBERON:0013473	70.60	gold quality
lower esophagus muscularis layer	UBERON:0035833	70.55	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-7051	yes	377.73
E-MTAB-7052	yes	88.65
E-MTAB-6678	yes	10.94
E-ANND-3	yes	10.24
E-MTAB-6524	no	130.91
E-GEOD-99795	no	111.26

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	12.8	low
Nucleus accumbens	tissue	10.5
Hippocampus	tissue	10.4	not detected
Postcentral gyrus	tissue	10.4
Tonsil	tissue	10.0	medium
Testis	tissue	9.4	high
Lymph node	tissue	9.3	low
Choroid plexus	tissue	9.2
Locus coeruleus	tissue	9.0
Thymus	tissue	7.9
Appendix	tissue	6.4	low
Rectum	tissue	5.0	medium
Spleen	tissue	5.0	not detected
Skeletal muscle	tissue	4.4	not detected
Placenta	tissue	4.1	low
Colon	tissue	3.3	medium
Small intestine	tissue	3.3	low
Skin 1	tissue	3.2	low
Salivary gland	tissue	3.2	low
Basal ganglia	tissue	3.0	not detected
Putamen	tissue	2.8
Breast	tissue	2.6	not detected
Stomach 1	tissue	2.6	not detected
Retina	tissue	2.6
Duodenum	tissue	2.4	medium
Hippocampal formation	tissue	2.3
Olfactory bulb	tissue	2.3
Ventral forebrain	tissue	2.2
Ovary	tissue	2.0	low
Esophagus	tissue	2.0	medium
Spinal cord	tissue	2.0
Fallopian tube	tissue	2.0	low
Septum	tissue	2.0
Amygdala	tissue	1.9
Entorhinal cortex	tissue	1.9
Cerebral cortex	tissue	1.8	not detected
Medulla oblongata	tissue	1.8
Retrosplenial and cingulate cortex	tissue	1.8
Temporal cortex	tissue	1.8
Pons	tissue	1.7
Urinary bladder	tissue	1.7	low
Midbrain	tissue	1.7
Hypothalamus	tissue	1.7
Smooth muscle	tissue	1.6	low
Motor cortex	tissue	1.6
Superior colliculi	tissue	1.6
Cerebellum	tissue	1.6	not detected
Substantia nigra	tissue	1.6
Thyroid gland	tissue	1.6	not detected
Somatosensory cortex	tissue	1.6
Retrosplenial cortex	tissue	1.6
Occipital cortex	tissue	1.6
Prefrontal cortex	tissue	1.5
Endometrium 1	tissue	1.5	not detected
Frontal cortex	tissue	1.5
Gallbladder	tissue	1.5	low
Prostate	tissue	1.5	not detected
Periaqueductal gray	tissue	1.5
Thalamus	tissue	1.4
Lung	tissue	1.4	not detected

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Piriform cortex (20.2), Parieto-temporal junction (white matter) (20.0), Area postrema (18.5), Area striata (white matter) (17.2), Temporal white matter (17.1).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CDKN2A, E2F1, E2F4

miRNA regulators (miRDB)

Targeting FANCD2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

27 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-155-5P	99.35	70.16	1509
HSA-MIR-148A-5P	99.30	68.27	1141
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-196A-3P	99.19	67.34	1204
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6859-5P	98.99	68.07	2049
HSA-MIR-583	98.71	67.44	1791
HSA-MIR-4773	98.35	67.30	1710
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-6511A-5P	98.13	67.47	1770
HSA-MIR-219B-5P	97.91	65.80	531
HSA-MIR-618	97.62	67.46	861
HSA-MIR-3928-3P	97.61	66.53	1096
HSA-MIR-4253	97.48	65.11	692
HSA-MIR-6862-5P	97.48	64.84	713
HSA-MIR-4286	97.20	64.37	1587
HSA-MIR-4661-3P	96.81	66.02	342
HSA-MIR-6888-5P	95.89	63.78	831

Functional genomics

gnomAD constraint: pLI 2.77e-19, LOEUF 0.777, missense Z 1.76 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000675286 splits into 5 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
3:10,028,658–10,043,585	435 / 421.9	1.03	no
3:10,043,586–10,049,505	108 / 174.1	0.62	no
3:10,052,387–10,062,206	110 / 114.4	0.96	no
3:10,062,207–10,064,811	59 / 111.9	0.53	no
3:10,064,812–10,101,259	796 / 879.4	0.91	no
ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map
DepMap (CRISPR cell-line fitness): dependent in 13.3% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): OCI-LY-19 (-1.954), SU-DHL-10 (-1.536), SU-DHL-8 (-1.515), YCUB-2 (-1.371), NRH-UPS2 (-1.234), EBC-1 (-1.194), HNT-34 (-1.134), CCLF_PEDS_0003_T (-1.129), HCC1187 (-1.112), OCI-AML3 (-1.042), EW-7 (-1.034), UWB1.289 (-1.008), SU-DHL-5 (-0.986), SKNO-1 (-0.959), HUP-T4 (-0.925).

Literature-anchored findings (GeneRIF, showing 40)

• may be a branch point in DNA damage response (PMID:12042798)
• interacts with BRCA1 and RAD51 in S phase cell lines (PMID:12239151)
• NBS1 and FANCD2 cooperate in two distinct cellular functions, one involved in the DNA crosslink response and one involved in the S-phase checkpoint response (PMID:12447395)
• Direct interaction between FANCE and FANCD2 involving an amino-terminal region of FANCD2 was demonstrated; this interaction may provide a link between the FA protein complex and its downstream targets. (PMID:12649160)
• Fancd2 is essential during embryogenesis to prevent inappropriate apoptosis in neural cells and other tissues undergoing high levels of proliferative expansion, implicating this mechanism in the congenital abnormalities observed in human infants with FA. (PMID:14667412)
• The transient slow-down of DNA synthesis was abolished in cells lacking ATR, whereas CHK1-siRNA-treated cells, NBS1 or Fanconi anemia cells showed partial S-phase arrest. (PMID:14988723)
• FANCD2 may have a role in the cellular response to stalled replication forks or in the repair of replication-associated double-strand breaks, irrespective of the type of primary DNA lesion (PMID:15115758)
• Bloom syndrome protein and FANCD2 colocalise and co-immunoprecipitate following treatment with either DNA crosslinkers or agents inducing replication arrest (PMID:15257300)
• ATR checkpoint kinase and RPA1 are required for efficient FANCD2 monoubiquitination (PMID:15314022)
• FANCD2, which is activated by the Fanconi anemia complex, is required to maintain the G2 checkpoint (PMID:15377654)
• The carboxy terminus of FANCD2-44 plays a critical role in sensing or repairing DNA damage. (PMID:15454491)
• Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair. (PMID:15650050)
• FANCD2 mediates double strand DNA break repair independently of BRCA2- and Rad51-associated homologous recombination (PMID:15671039)
• FANCD2 bound to DNA with specificity for certain structures: double strand DNA ends and Holliday junctions (PMID:15849361)
• FANCD2 mutations were also common in Microsatellite instability+ Therapy-related acute myeloid leukemia/myelodysplastic syndrome (PMID:15886296)
• FANCC, FANCE, and FANCD2 form a ternary complex in the Fanconi anemia DNA damage response pathway (PMID:16127171)
• FANCL, via its WD40 region, binds the FA complex and, via its PHD, recruits an as-yet-unidentified E2 for mono-ubiquitination of FANCD2 (PMID:16474167)
• FANCD2 single nucleotide polymorphisms may be associated with sporadic breast cancer risk (PMID:16679306)
• These findings support the functional connection of ATM/ATR kinases and FANCD2 in the DNA damage response and support a role for the FA pathway in the coordination of the S phase of the cell cycle. (PMID:16943440)
• FANCD2 expression is absent in 10-20% of sporadic and BRCA1-related breast cancers, indicating that somatic inactivating (epi)genetic events in FANCD2 may be important in both sporadic and hereditary breast carcinogenesis (PMID:17333336)
• total absence of FANCD2 does not exist in FA-D2 patients, because of constraints on viable combinations of FANCD2 mutations (PMID:17436244)
• Knocking-down FANCD2 gene expression increases sensitivity of cancer cells to mitomycin C and to less extent to gamma-rays. Cell lines with significant FANCD2 depletion revealed decreased recurrence capacity. (PMID:17643815)
• Study found that Fanconi anemia pathway activation is triggered mainly by the HPV type 16 (HPV-16) E7 oncoprotein and is associated with an enhanced formation of large FANCD2 foci and recruitment of FANCD2 as well as FANCD1/BRCA2 to chromatin. (PMID:17898070)
• Loss of CHK1 function impedes DNA dmage-induced FANCD2 monoubiquitination but normalizes the abnormal G2 arrest in Fanconi anemia. (PMID:18029388)
• FANCG promotes formation of a newly identified protein complex containing BRCA2, FANCD2 and XRCC3. (PMID:18212739)
• chromatin remodeling protein, Tip60, interacts directly with the FANCD2 protein (PMID:18263878)
• Snm1B interacts with the Mre11-Rad50-Nbs1 (MRN) complex and with FancD2 further substantiating its role as a checkpoint/DNA repair protein. (PMID:18469862)
• Carcinogen-mediated suppression of FANCD2 gene expression provides a plausible molecular mechanism for CIN in bronchogenic carcinogenesis. (PMID:18475298)
• In contrast to other DNA damaging agents, ethanol/acetaldehyde generated DNA strand breaks without inducing ubiquitination of FANCD2, despite increasing protein levels in the nucleus. (PMID:18482162)
• Following ERCC1 depletion, FANCD2-Ub formation is reduced and FANCD2 foci are eliminated. (PMID:18672388)
• no defect in FANCD2 ubiquitination, BRCA2 and FANCJ expression; absence of FANCN protein in three cell lines: HT, Sudhl4 and JEKO-1. (PMID:19011769)
• Resutls show a role of FANCD2 in ALT, evidence shows that knockdown of FANCD2 rapidly causes telomere dysfunction in cells that rely on ALT to maintain telomeres. (PMID:19047177)
• unlike cells defective in other core complex members, FANCM(-/-) cells were proficient in monoubiquitinating FANCD2 (PMID:19423727)
• Data show that FANCD2 and FANCI specifically associate with common fragile site loci irrespective of whether the chromosome is broken, and that these loci are frequently interlinked through BLM-associated ultra-fine DNA bridges through mitosis. (PMID:19465922)
• the role of the central FA protein D2 (FANCD2) in determining cellular radioresistance (PMID:19466639)
• Our results suggest that large genomic deletions in BRIP1/FANCJ, PALB2/FANCN, and FANCD2 do not contribute significantly to the familial breast cancer risk in the Dutch population (PMID:19504183)
• the FANCI-FANCD2 complex may participate in repair of damaged replication forks through its preferential recognition of branched structures. (PMID:19561358)
• Inhibition of MRE11, NBS1 or RAD50 leads to a destabilization of FANCD2. (PMID:19609304)
• The successful detection of BRCA1, FANCD2, and RAD51 foci in breast cancer biopsies irradiated ex vivo, is reported. (PMID:19671671)
• PCNA may function as a molecular platform to facilitate the mono-ubiquitination of FANCD2 and activation of the FA-BRCA pathway (PMID:19704162)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fancd2	ENSDARG00000053574
mus_musculus	Fancd2	ENSMUSG00000034023
rattus_norvegicus	Fancd2	ENSRNOG00000061085
drosophila_melanogaster	Fancd2	FBGN0038827
caenorhabditis_elegans		WBGENE00012767

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2448480) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 46 distinct phenotype terms.

Mouse phenotype (MP)	Records
small testis	3
microphthalmia	3
postnatal growth retardation	3
decreased hematopoietic stem cell number	3
decreased body weight	2
increased carcinoma incidence	2
abnormal seminiferous tubule morphology	2
abnormal bone marrow cell morphology/development	2
oligozoospermia	2
fetal growth retardation	2
abnormal male meiosis	2
abnormal spermatocyte morphology	2
increased sensitivity to induced cell death	2
increased adenoma incidence	2
perinatal lethality, incomplete penetrance	2
enlarged spleen	1
weakness	1
small ovary	1
abnormal ovarian follicle morphology	1
abnormal testis morphology	1
decreased body size	1
persistence of hyaloid vascular system	1
decreased locomotor activity	1
anemia	1
infertility	1

+21 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Gallus gallus	Q68Y81	57.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
EMC3-AS1	ncRNA	442075
EMC3	protein-coding	55831
FANCD2OS	protein-coding	115795
BRK1	protein-coding	55845
VHL	protein-coding	7428

Protein

Protein identifiers

Fanconi anemia group D2 protein — Q9BXW9 (reviewed: Q9BXW9)

All UniProt accessions (4): A0A6Q8PFY3, Q9BXW9, F8WE37, H7BZJ7

UniProt curated annotations — full annotation on UniProt →

Function. Required for maintenance of chromosomal stability. Promotes accurate and efficient pairing of homologs during meiosis. Involved in the repair of DNA double-strand breaks, both by homologous recombination and single-strand annealing. The FANCI-FANCD2 complex binds and scans double-stranded DNA (dsDNA) for DNA damage; this complex stalls at DNA junctions between double-stranded DNA and single-stranded DNA. May participate in S phase and G2 phase checkpoint activation upon DNA damage. Plays a role in preventing breakage and loss of missegregating chromatin at the end of cell division, particularly after replication stress. Required for the targeting, or stabilization, of BLM to non-centromeric abnormal structures induced by replicative stress. Promotes BRCA2/FANCD1 loading onto damaged chromatin. May also be involved in B-cell immunoglobulin isotype switching.

Subunit / interactions. Homodimer; cannot be ubiquitinated and does not bind DNA. Part of a FANCI-FANCD2 heterodimeric complex that binds and scans dsDNA for DNA damage. Interacts directly with FANCE and FANCI. Interacts with USP1 and MEN1. The ubiquitinated form specifically interacts with BRCA1 and BLM. Both the nonubiquitinated and the monoubiquitinated forms interact with BRCA2; this interaction is mediated by phosphorylated FANCG and the complex also includes XCCR3. The ubiquitinated form specifically interacts with MTMR15/FAN1 (via UBZ-type zinc finger), leading to recruit MTMR15/FAN1 to sites of DNA damage. Interacts with DCLRE1B/Apollo. Interacts with POLN. Interacts with UHRF1 and UHRF2; these interactions promote FANCD2 activation.

Subcellular location. Nucleus.

Tissue specificity. Highly expressed in germinal center cells of the spleen, tonsil, and reactive lymph nodes, and in the proliferating basal layer of squamous epithelium of tonsil, esophagus, oropharynx, larynx and cervix. Expressed in cytotrophoblastic cells of the placenta and exocrine cells of the pancreas (at protein level). Highly expressed in testis, where expression is restricted to maturing spermatocytes.

Post-translational modifications. Monoubiquitinated on Lys-561 during S phase and upon genotoxic stress by FANCL in complex with E2 ligases UBE2T or UBE2W (isoform 1 and isoform 2). Deubiquitinated by USP1 as cells enter G2/M, or once DNA repair is completed. Monoubiquitination requires the joint intervention of the FANC core complex, including FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, and FANCM, and proteins involved in cell cycle checkpoints and DNA repair, including RPA1, ATR, CHEK1 and BRCA1, and is mediated by FANCL/PHF9. Monoubiquitination prevents DNA release from the FANCI-FANCD2 complex. FANCD2 is only ubiquitinated in the FANCI-FANCD2 complex and the monoubiquitination of FANCD2 is promoted by phosphorylation of FANCI. Ubiquitination is required for binding to chromatin, interaction with BRCA1, BRCA2 and MTMR15/FAN1, DNA repair, and normal cell cycle progression, but not for phosphorylation on Ser-222 or interaction with MEN1. Phosphorylated in response to various genotoxic stresses by ATM and/or ATR. Upon ionizing radiation, phosphorylated by ATM on Ser-222 and Ser-1404. Phosphorylation on Ser-222 is required for S-phase checkpoint activation, but not for ubiquitination, foci formation, or DNA repair. In contrast, phosphorylation by ATR on other sites may be required for ubiquitination and foci formation.

Disease relevance. Fanconi anemia complementation group D2 (FANCD2) [MIM:227646] A disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The C-terminal 24 residues of isoform 2 are required for its function.

Miscellaneous. Less abundant than isoform 2, may be not functional.

Similarity. Belongs to the Fanconi anemia protein FANCD2 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9BXW9-2	2	yes
Q9BXW9-1	1
Q9BXW9-3	3
Q9BXW9-4	4

RefSeq proteins (6): NP_001018125, NP_001306913, NP_001361182, NP_001361183, NP_001361184, NP_149075 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029448	FANCD2	Family

Pfam: PF14631

UniProt features (155 total): helix 77, strand 17, sequence variant 15, modified residue 12, turn 10, mutagenesis site 6, region of interest 5, splice variant 5, sequence conflict 3, compositionally biased region 3, chain 1, cross-link 1

Structure

Experimental structures (PDB)

13 structures by resolution:

PDB	Title	Method	Resolution (Å)
8A9J	Cryo-EM structure of USP1-UAF1 bound to FANCI and mono-ubiquitinated FANCD2 without ML323 …	ELECTRON MICROSCOPY	2.8
8A9K	Cryo-EM structure of USP1-UAF1 bound to FANCI and mono-ubiquitinated FANCD2 with ML323 …	ELECTRON MICROSCOPY	2.85
6VAD	Fanconi Anemia ID complex	ELECTRON MICROSCOPY	3.3
6VAA	Structure of the Fanconi Anemia ID complex bound to ICL DNA	ELECTRON MICROSCOPY	3.4
6VAE	Mono-ubiquitinated Fanconi Anemia ID complex bound to ICL DNA	ELECTRON MICROSCOPY	3.6
7AY1	Cryo-EM structure of USP1-UAF1 bound to mono-ubiquitinated FANCD2, and FANCI	ELECTRON MICROSCOPY	3.7
6VAF	Structure of mono-ubiquitinated FANCD2 bound to non-ubiquitinated FANCI and to DNA	ELECTRON MICROSCOPY	3.9
7ZF1	Structure of ubiquitinated FANCI in complex with FANCD2 and double-stranded DNA	ELECTRON MICROSCOPY	4.14
7KZS	Structure of the human fanconi anaemia Core-UBE2T-ID-DNA complex in open state	ELECTRON MICROSCOPY	4.2
7KZT	Structure of the human fanconi anaemia Core-UBE2T-ID-DNA complex in intermediate state	ELECTRON MICROSCOPY	4.2
7KZV	Structure of the human fanconi anaemia Core-UBE2T-ID-DNA complex in closed state	ELECTRON MICROSCOPY	4.2
7KZQ	Structure of the human Fanconi anaemia Core-ID complex	ELECTRON MICROSCOPY	4.3
7KZR	Structure of the human Fanconi Anaemia Core-UBE2T-ID complex	ELECTRON MICROSCOPY	4.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BXW9-F1	77.24	0.33

Human Protein Atlas

Protein class: Predicted intracellular proteins, Cancer-related genes, Disease related genes, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nuclear bodies; nucleoplasm; cytosol; nucleoli

Antibody reliability (HPA): IH approved · IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (13)

Type	Positions
Phosphoserine	222, 592, 594, 717, 1257, 1401, 1404, 1412, 1423, 1435, 8
Phosphothreonine	1426
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in ubiquitin)	561

Mutagenesis-validated functional residues (6)

Position	Phenotype
222	reduces phosphorylation by atm. no effect on ubiquitination, foci formation or dna repair ability, but impairs s-phase checkpoint …
561	abolishes ubiquitination; impairs chromatin binding, foci formation and dna repair. abolishes interaction with mtmr15/fan1. no effect on …
1257	no effect on phosphorylation by atm.
1401	reduces phosphorylation by atm; when associated with a-1404 and a-1418.
1404	reduces phosphorylation by atm; when associated with a-1401 and a-1418.
1418	reduces phosphorylation by atm; when associated with a-1401 and a-1404.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 7; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

7 pathways:

ID	Pathway	Evidence
R-HSA-6783310	Fanconi Anemia Pathway	curated
R-HSA-6796648	TP53 Regulates Transcription of DNA Repair Genes	curated
R-HSA-73894	DNA Repair	—
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-73857	RNA Polymerase II Transcription	—
R-HSA-3700989	Transcriptional Regulation by TP53	—

MSigDB gene sets: 568 (showing top): PID_FANCONI_PATHWAY, GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_REGULATION_OF_CELL_ACTIVATION, E2F_Q4, GOBP_CHROMOSOME_ORGANIZATION, GOBP_RESPONSE_TO_IONIZING_RADIATION, HORIUCHI_WTAP_TARGETS_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, E2F4DP1_01, GOBP_INFLAMMATORY_RESPONSE, GOBP_CELL_CYCLE_PHASE_TRANSITION, TGACCTY_ERR1_Q2, KAUFFMANN_DNA_REPAIR_GENES, GOBP_MITOTIC_INTRA_S_DNA_DAMAGE_CHECKPOINT_SIGNALING, CREB_Q4

GO Biological Process (7): homologous chromosome pairing at meiosis (GO:0007129), response to gamma radiation (GO:0010332), mitotic intra-S DNA damage checkpoint signaling (GO:0031573), interstrand cross-link repair (GO:0036297), double-strand break repair involved in meiotic recombination (GO:1990918), DNA repair (GO:0006281), DNA damage response (GO:0006974)

GO Molecular Function (2): DNA polymerase binding (GO:0070182), protein binding (GO:0005515)

GO Cellular Component (6): chromatin (GO:0000785), condensed chromosome (GO:0000793), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), nuclear body (GO:0016604)

Reactome top-level categories

5 top-level categories:

Category	Pathways
DNA Repair	1
Transcriptional Regulation by TP53	1
RNA Polymerase II Transcription	1
Generic Transcription Pathway	1
Gene expression (Transcription)	1

GO top-level categories

20 GO namespaces:

Category	Terms
chromosome	2
cellular anatomical structure	2
nuclear lumen	2
intracellular membraneless organelle	2
homologous chromosome segregation	1
chromosome organization involved in meiotic cell cycle	1
response to ionizing radiation	1
mitotic S phase	1
mitotic DNA damage checkpoint signaling	1
DNA repair	1
double-strand break repair	1
reciprocal meiotic recombination	1
meiotic cell cycle process	1
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
enzyme binding	1
binding	1
intracellular membrane-bounded organelle	1
nucleoplasm	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 15 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO term	NS	Evidence
response to gamma radiation	BP	direct assay
nuclear body	CC	direct assay
nucleolus	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
DNA polymerase binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 2,210 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FANCD2	FANCI	Q9NVI1	980
FANCD2	FANCA	O15360	977
FANCD2	FANCL	Q9NW38	975
FANCD2	FANCC	Q00597	972
FANCD2	FANCG	O15287	969
FANCD2	FANCM	Q8IYD8	966
FANCD2	BRIP1	Q9BX63	951
FANCD2	BRCA2	P51587	951
FANCD2	FANCF	Q9NPI8	951
FANCD2	FANCB	Q8NB91	939
FANCD2	FANCE	Q9HB96	930
FANCD2	BRCA1	P38398	930
FANCD2	FAAP24	Q9BTP7	918
FANCD2	RAD51	Q06609	914
FANCD2	PALB2	Q86YC2	904

IntAct

Human interaction partners of FANCD2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

24 partners by confidence:

Partner	Interaction type	MIscore	Records
BRCA2	physical association	0.690	14
FSCN1	physical association	0.650	3
MRE11	physical association	0.650	3
NBN	association	0.630	6
FANCE	physical association	0.620	3
CEBPD	association	0.610	6
EGFR	physical association	0.600	2
FANCI	physical association	0.590	1
BRCA1	physical association	0.580	2
MEN1	physical association	0.520	4
FANCG	association	0.350	2
FBXW7	proximity	0.270	4
SMAD4	proximity	0.270	4
SMARCA4	proximity	0.270	4
SPOP	proximity	0.270	4
AKT1	proximity	0.270	1
BRAF	proximity	0.270	1
H2AX	colocalization	0.270	1
PTEN	proximity	0.270	1
PTPN11	proximity	0.270	1
TP53	proximity	0.270	1
TNFRSF1A	physical association	0.000	1
TNFRSF1B	physical association	0.000	1
TRAF6	physical association	0.000	1

BioGRID (1,129 interactions; top human partners by supporting records in a sample of 600 records): FANCI (Affinity Capture-Western; 15 records), RBBP8 (Affinity Capture-Western; 12 records), BRCA2 (Affinity Capture-Western; 9 records), MCM3 (Affinity Capture-Western; 8 records), FANCL (Biochemical Activity; 6 records), UHRF1 (Co-localization; 6 records), ATP5A1 (Affinity Capture-MS; 5 records), BRIP1 (Affinity Capture-Western; 5 records), FANCE (Affinity Capture-Western; 5 records), RAD51 (Affinity Capture-Western; 5 records), HIST1H4A (Reconstituted Complex; 4 records), MCM2 (Co-localization; 4 records), MCM5 (Affinity Capture-MS; 4 records), TPTE (Affinity Capture-MS; 4 records), USP1 (Co-fractionation; 4 records)

SIGNOR signaling

showing 15 of 27 signaling interactions:

A	Effect	B	Mechanism
MEN1	up-regulates	FANCD2	binding
CHEK1	“up-regulates activity”	FANCD2	phosphorylation
ATR	up-regulates	FANCD2	phosphorylation
BRCA1	“up-regulates activity”	FANCD2	ubiquitination
“BRCA1-BARD1 complex”	“up-regulates activity”	FANCD2	ubiquitination
FANCD2	“up-regulates activity”	BRCA2	binding
“Fanconi anemia core complex”	“up-regulates activity”	FANCD2	ubiquitination
FANCL	“up-regulates activity”	FANCD2	ubiquitination
FANCD2	“up-regulates activity”	BRCA2	relocalization
FANCD2	“form complex”	“D1-D2-G-X3 complex”	binding
FANCD2	“form complex”	“Fanconi anemia ID complex”	binding
USP1	“down-regulates activity”	FANCD2	deubiquitination
CSNK2A1	“down-regulates activity”	FANCD2	phosphorylation
RAD18	“up-regulates activity”	FANCD2	ubiquitination
ATM	up-regulates	FANCD2	phosphorylation

Protein complexes (CORUM) (4)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

4 complexes by size:

Complex	Subunits	Members
★ AKT1 multiprotein complex	7	PHLPP2, USP1, WDR48, AKT1, FANCD2, FANCI, PHLPP1
MDC1-MRN-ATM-FANCD2 complex	6	MRE11, NBN, RAD50, ATM, FANCD2, MDC1
FANCG-BRCA2-FANCD2-XRCC3 complex	4	BRCA2, FANCD2, FANCG, XRCC3
FANCI-FANCD2 complex	2	FANCD2, FANCI

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 24 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	5	30.5×	2e-05
Meiotic recombination	5	27.0×	3e-05
G2/M DNA damage checkpoint	5	25.0×	3e-05
Interleukin-4 and Interleukin-13 signaling	5	21.4×	6e-05
Cell Cycle	5	7.5×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
double-strand break repair	6	50.8×	1e-06
double-strand break repair via homologous recombination	5	32.5×	7e-05
DNA damage response	8	17.8×	3e-06
DNA repair	5	13.3×	8e-04
positive regulation of gene expression	5	8.1×	5e-03
negative regulation of apoptotic process	5	7.2×	7e-03

Disease & clinical

Genetic variants

Variant evidence for FANCD2: 2,110 ClinVar records (259 pathogenic / likely pathogenic); 2 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

2,110 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	132
Likely pathogenic	127
Uncertain significance	751
Likely benign	788
Benign	105

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 259 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
929642	NM_001018115.3(FANCD2):c.376A>G (p.Ser126Gly)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
929662	NM_001018115.3(FANCD2):c.2661del (p.Glu888fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
12041	NM_001018115.3(FANCD2):c.958C>T (p.Gln320Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
929659	NM_001018115.3(FANCD2):c.1948-16T>G	Pathogenic	criteria provided, multiple submitters, no conflicts	3
1322883	NM_001018115.3(FANCD2):c.3500G>A (p.Trp1167Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1338373	NM_001018115.3(FANCD2):c.3385C>T (p.Gln1129Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2982057	NM_001018115.3(FANCD2):c.38_39del (p.Lys13fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
809378	NM_001018115.3(FANCD2):c.3224+1G>T	Likely pathogenic	criteria provided, multiple submitters, no conflicts	5
1179148	NM_001018115.3(FANCD2):c.1279-2A>G	Likely pathogenic	criteria provided, multiple submitters, no conflicts	4
2653512	NM_001018115.3(FANCD2):c.2269+1G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	4
929644	NM_001018115.3(FANCD2):c.696-121C>G	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
1523794	NM_001018115.3(FANCD2):c.64+2T>G	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
2041518	NM_001018115.3(FANCD2):c.3560+1G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
623166	NM_001018115.3(FANCD2):c.3095del (p.Asn1032fs)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
1224523	NM_001018115.3(FANCD2):c.206-1G>T	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2

Per-variant reference — Sugi Variant

Explore FANCD2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 32 predictions of 3,722):

Position(s)	Effect	Δscore	Sites
3:10028623–10028624	acceptor_loss	1.0000	6
3:10028722–10028723	donor_loss	1.0000	5
3:10032830–10032831	acceptor_loss	1.0000	6
3:10032969	donor_gain	1.0000
3:10032973–10032974	donor_loss	1.0000	5
3:10034683	acceptor_gain	1.0000
3:10034693	acceptor_gain	1.0000
3:10035234–10035235	donor_loss	1.0000	5
3:10039270	acceptor_gain	1.0000
3:10039273	acceptor_gain	1.0000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (validation)	unfavorable	0.00015
Kidney Chromophobe (TCGA)	unfavorable	0.000189
Lung Adenocarcinoma (validation)	unfavorable	0.000614

Disease associations

OMIM: gene MIM:613984 | disease phenotypes: MIM:227650, MIM:193300, MIM:263400, MIM:227646, MIM:601626, MIM:114480

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
Fanconi anemia complementation group D2	Definitive	Autosomal recessive	6
Fanconi anemia	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
Fanconi anemia complementation group D2	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (22 panels, 18 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

22 panels:

Panel	Rating
Adult solid tumours cancer susceptibility	green
COVID-19 research	green
Childhood solid tumours	green
Childhood solid tumours cancer susceptibility	green
Cytopenias and congenital anaemias	green
DDG2P	green
Fanconi anaemia or Bloom syndrome	green
Fetal anomalies	green
Haematological malignancies cancer susceptibility	green
Haematological malignancies for rare disease	green
Head and neck cancer pertinent cancer susceptibility	green
IUGR and IGF abnormalities	green
Limb disorders	green
Monogenic short stature	green
Neurofibromatosis Type 1	green
Pigmentary skin disorders	green
Radial dysplasia	green
Severe microcephaly	green
Hypotonic infant	amber
Intellectual disability	amber
Leukodystrophy, childhood onset	amber
Paediatric disorders	amber

Mondo (7): Fanconi anemia (MONDO:0019391), von Hippel-Lindau disease (MONDO:0008667), Chuvash polycythemia (MONDO:0009892), Fanconi anemia complementation group D2 (MONDO:0009214), acute myeloid leukemia (MONDO:0018874), hereditary breast carcinoma (MONDO:0016419), Fanconi anemia complementation group A (MONDO:0009215)

Orphanet (5): Fanconi anemia (Orphanet:84), Chuvash erythrocytosis (Orphanet:238557), Von Hippel-Lindau disease (Orphanet:892), Acute myeloid leukemia (Orphanet:519), Hereditary breast cancer (Orphanet:227535)

HPO phenotypes

showing 60 of 143 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000035	Abnormal testis morphology
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000072	Hydroureter
HP:0000075	Renal duplication
HP:0000079	Abnormality of the urinary system
HP:0000081	Duplicated collecting system
HP:0000083	Renal insufficiency
HP:0000085	Horseshoe kidney
HP:0000086	Ectopic kidney
HP:0000104	Renal agenesis
HP:0000125	Pelvic kidney
HP:0000130	Abnormality of the uterus
HP:0000135	Hypogonadism
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000364	Hearing abnormality
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000453	Choanal atresia
HP:0000478	Abnormality of the eye
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000492	Abnormal eyelid morphology
HP:0000504	Abnormality of vision
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000520	Proptosis
HP:0000568	Microphthalmia
HP:0000581	Blepharophimosis
HP:0000582	Upslanted palpebral fissure
HP:0000601	Hypotelorism
HP:0000639	Nystagmus
HP:0000813	Bicornuate uterus
HP:0000815	Hypergonadotropic hypogonadism
HP:0000864	Abnormality of the hypothalamus-pituitary axis
HP:0000957	Cafe-au-lait spot
HP:0000978	Bruising susceptibility
HP:0001000	Abnormal skin pigmentation
HP:0001017	Anemic pallor
HP:0001053	Hypopigmented skin patches
HP:0001172	Abnormal thumb morphology
HP:0001177	Preaxial hand polydactyly
HP:0001199	Triphalangeal thumb
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay

GWAS associations

2 associations:

Study	Trait	p-value
GCST002422_5	Alzheimer’s disease	2e-6
GCST008159_6	Waist-to-hip ratio adjusted for BMI	9e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors

5 disease descriptors:

Descriptor	Name	Tree numbers
D005199	Fanconi Anemia	C15.378.050.085.080.280; C15.378.190.223.500.500.280; C16.320.077.280; C18.452.284.280
D015470	Leukemia, Myeloid, Acute	C04.557.337.539.275; C15.378.508.539.275
D006623	von Hippel-Lindau Disease	C10.562.925; C14.907.077.925; C16.131.077.245.750; C16.320.184.750
C562840	Breast Cancer, Familial *(supp.)*
C563918	Erythrocytosis, Familial, 2 *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2157857 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (2 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.71	Kd	1962	nM	CHEMBL3752910
5.71	ED50	1962	nM	CHEMBL3752910
5.64	Kd	2278	nM	CHEMBL5653589
5.64	ED50	2278	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 5 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148368: Binding affinity to human FANCD2 incubated for 45 mins by Kinobead based pull down assay	kd	1.9619	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148368: Binding affinity to human FANCD2 incubated for 45 mins by Kinobead based pull down assay	kd	2.2784	uM

CTD chemical–gene interactions

98 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	3
Endosulfan	affects expression, decreases reaction, decreases expression, increases expression	3
Mitomycin	decreases activity, increases response to substance, affects ubiquitination, decreases reaction, increases expression (+1 more)	3
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride	decreases expression	2
Bortezomib	decreases expression	2
Resveratrol	affects cotreatment, increases expression	2
Acetaminophen	decreases expression, increases expression	2
Cisplatin	increases expression, increases ubiquitination	2
Doxorubicin	decreases expression, affects reaction, affects expression, affects response to substance	2
Oxygen	decreases expression	2
Rotenone	increases expression, decreases expression	2
Particulate Matter	increases ubiquitination, affects cotreatment, decreases expression, increases abundance, affects reaction (+1 more)	2
FR900359	affects phosphorylation	1
pradimicin-IRD	affects response to substance, decreases expression, affects expression	1
lasiocarpine	decreases expression, increases metabolic processing	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
propionaldehyde	decreases expression	1
bisphenol A	decreases expression	1
diepoxybutane	decreases activity, increases response to substance	1
N(4)-hydroxycytidine	increases expression	1
riddelliine	decreases expression, increases metabolic processing	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
monomethylarsonic acid	increases response to substance, decreases activity	1
nickel chloride	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2160735	Binding	Inhibition of CDDP-induced FANCD2 monoubiquitination in human HeLa cells at 9 uM after 18 hrs by Western blot analysis	The antitumor agent doxorubicin binds to Fanconi anemia group F protein. — *Bioorg Med Chem*

Cellosaurus cell lines

12 cell lines: 9 cancer cell line, 3 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_AK49	PD20 RV:D2	Transformed cell line	Male
CVCL_B1RX	Abcam HeLa FANCD2 KO	Cancer cell line	Female
CVCL_B8FR	Abcam HCT 116 FANCD2 KO	Cancer cell line	Male
CVCL_B8VL	Abcam MCF-7 FANCD2 KO	Cancer cell line	Female
CVCL_B9HY	Abcam A-549 FANCD2 KO	Cancer cell line	Male
CVCL_D6BI	HyCyte HeLa KO-hFANCD2	Cancer cell line	Female
CVCL_D6CM	HyCyte SiHa KO-hFANCD2	Cancer cell line	Female
CVCL_G041	GM16756	Transformed cell line	Male
CVCL_G042	GM16633	Transformed cell line	Male
CVCL_KT56	HeLa SilenciX FancD2	Cancer cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00190697	Phase 4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00277160	Phase 4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00727961	Phase 4	COMPLETED	A Study to Evaluate Efficacy and Tolerance of Caelyx in Patients With Epithelial Ovarian Cancer. (Study P04072)(COMPLETED)
NCT00740116	Phase 4	COMPLETED	Tranexamic Acid in Surgery of Advanced Ovarian Cancer
NCT00817479	Phase 4	COMPLETED	Tumor Gene Expression in Women With Ovarian Cancer
NCT01432015	Phase 4	COMPLETED	Fosaprepitant Versus Aprepitant in the Prevention of Chemotherapy Induced Nausea and Vomiting
NCT01706120	Phase 4	UNKNOWN	Study of Clinical and Biological Prognostic Factors in Patients With Ovarian Cancer Receiving Carboplatin +Paclitaxel With Bevacizumab
NCT01932125	Phase 4	COMPLETED	An Interventional Study of Avastin (Bevacizumab) in Patients With Advanced/Metastatic Epithelial Ovarian Cancer, Fallopian Tube Cancer or Primary Peritoneal Cancer
NCT01953107	Phase 4	COMPLETED	Oral Iron vs. Placebo in Newly Diagnosed Gynecologic Oncology Patients Who Are Surgical Candidates.
NCT02035345	Phase 4	TERMINATED	Slowed Carboplatin Infusion for Ovarian Cancer Patients Receiving Carboplatin Re-Treatment
NCT02243059	Phase 4	WITHDRAWN	Magnetic Resonance Imaging for Lymph Node Staging in Ovarian Cancer
NCT03164980	Phase 4	TERMINATED	QoL-Comparison Between Trabectedin/PLD and Pt-based Therapy in Patients With Pt-sensitive Recurrent Ovarian Cancer
NCT03384511	Phase 4	COMPLETED	The Use of 18F-ALF-NOTA-PRGD2 PET/CT Scan to Predict the Efficacy and Adverse Events of Apatinib in Malignancies.
NCT03543462	Phase 4	COMPLETED	Diaphragmatic Resection And Gynecological Ovarian Neoplasm
NCT03752216	Phase 4	COMPLETED	NIraparib and Quality of LifE is a Longitudinal Study Evaluating in Real Life the Tolerability of Niraparib.
NCT03858166	Phase 4	TERMINATED	Efficacy and Safety of PEG-rhG-CSF Secondary Prophylaxis vs. Therapeutic Administration in Patients With Ovarian Cancer
NCT04024254	Phase 4	COMPLETED	A Study of Serum Folate Levels in Patients Treated With Olaparib
NCT04330040	Phase 4	COMPLETED	Prospective Multicentre Phase-IV Clinical Trial of Olaparib in Indian Patients With Ovarian and Metastatic Breast Cancer
NCT04352439	Phase 4	COMPLETED	Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving Neoadjuvant Chemotherapy
NCT05187208	Phase 4	UNKNOWN	PARP Inhibitor Oral Maintenance in Low-Risk Ovarian Cancer
NCT05606692	Phase 4	RECRUITING	Influences of Propofol and Sevoflurane Anesthesia in Ovarian Cancer (Anesthetics)
NCT05926336	Phase 4	UNKNOWN	The Effects of Using Different Anesthetics on the Prognosis of Primary Tumors and Its Mechanism of Action
NCT06412120	Phase 4	RECRUITING	Study Evaluating Safety, Tolerability, and Metabolism of Niraparib
NCT06871787	Phase 4	NOT_YET_RECRUITING	Near-Infrared Fluorescence Imaging With Indocyanine Green to Evaluate Bowel Anastomoses in Gynecologic Oncology Surgery
NCT06887933	Phase 4	NOT_YET_RECRUITING	A Trial to Evaluate the Safety of Niraparib Tablets in Adult Female Participants With Advanced or Relapsed Epithelial Ovarian Cancer
NCT07469202	Phase 4	NOT_YET_RECRUITING	CYTALUX Dose Extension Study
NCT06519786	Phase 3	UNKNOWN	Safety and Efficacy of Metformin for Treatment of Cytopenia in Children and Adolescents With Fanconi Anemia
NCT00001806	Phase 3	COMPLETED	Methods in Education for Breast Cancer Genetics
NCT00002477	Phase 3	UNKNOWN	Adjuvant Chemotherapy Compared With Observation in Treating Patients With Resected Early Stage Ovarian Epithelial Cancer
NCT00002568	Phase 3	COMPLETED	Combination Chemotherapy With or Without Surgery in Treating Patients With Stage III Ovarian Epithelial Cancer
NCT00002641	Phase 3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Soft Tissue Sarcoma
NCT00002717	Phase 3	COMPLETED	Paclitaxel and Cisplatin in Treating Patients With Stage III or Stage IV Ovarian Cancer or Primary Peritoneal Cancer
NCT00002764	Phase 3	COMPLETED	Surgery With or Without Combination Chemotherapy in Treating Patients With Lung Metastases From Soft Tissue Sarcoma
NCT00002819	Phase 3	TERMINATED	Chemotherapy With or Without Peripheral Stem Cell Transplantation in Treating Patients With Persistent Ovarian Epithelial Cancer
NCT00002894	Phase 3	COMPLETED	Platinum-based Chemotherapy With or Without Paclitaxel in Treating Patients With Relapsed Ovarian Cancer
NCT00002895	Phase 3	COMPLETED	Early Chemotherapy Based on CA 125 Level Alone Compared With Delayed Chemotherapy in Treating Patients With Recurrent Ovarian Epithelial , Fallopian Tube, or Primary Peritoneal Cancer
NCT00003120	Phase 3	COMPLETED	S9701 Paclitaxel in Treating Patients With Advanced Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Remission
NCT00003214	Phase 3	COMPLETED	Chemosensitivity Testing to Assign Treatment for Patients With Stage III or Stage IV Ovarian Cancer
NCT00003322	Phase 3	COMPLETED	Combination Chemotherapy in Treating Patients With Primary Peritoneal or Stage III Epithelial Ovarian Cancer
NCT00003636	Phase 3	COMPLETED	Chemotherapy Plus Surgery in Treating Patients With Stage III or Stage IV Ovarian, Peritoneal, or Fallopian Tube Cancer
NCT00003644	Phase 3	COMPLETED	Carboplatin Plus Paclitaxel With or Without Continued Low-Dose Paclitaxel in Treating Patients With Early-Stage Ovarian Cancer
NCT00003695	Phase 3	COMPLETED	Chemotherapy With or Without Surgery in Treating Patients With Stage II or Stage III Ovarian Cancer
NCT00003998	Phase 3	COMPLETED	Carboplatin Plus Paclitaxel or Docetaxel in Treating Patients With Ovarian Epithelial Cancer
NCT00004115	Phase 3	UNKNOWN	Monoclonal Antibody Therapy in Treating Patients With Ovarian Cancer or Primary Peritoneal Cancer in Remission Following Surgery and Chemotherapy
NCT00004166	Phase 3	COMPLETED	Amifostine in Treating Patients With Ovarian Epithelial Cancer Who Are Receiving Chemotherapy
NCT00004921	Phase 3	COMPLETED	High-Dose Chemotherapy Compared With Standard Chemotherapy in Treating Patients With Stage III or Stage IV Ovarian Epithelial Cancer That Has Been Removed During Surgery
NCT00004934	Phase 3	COMPLETED	Paclitaxel and Carboplatin With or Without Epirubicin in Treating Patients With Stage IIB, Stage III, or Stage IV Invasive Ovarian Epithelial, Fallopian Tube, or Peritoneal Cancer
NCT00005590	Phase 3	COMPLETED	Levofloxacin to Prevent Infection Following Chemotherapy in Treating Patients With Solid Tumors or Lymphoma
NCT00006356	Phase 3	TERMINATED	Chemotherapy With or Without Surgery in Treating Patients With Recurrent Ovarian Cancer
NCT00006453	Phase 3	COMPLETED	Carboplatin With or Without Gemcitabine in Treating Patients With Advanced Ovarian Epithelial Cancer That Has Not Responded to Previous Chemotherapy
NCT00006454	Phase 3	COMPLETED	Paclitaxel Plus Carboplatin With or Without Topotecan in Treating Patients With Stage IIB, Stage III, or Stage IV Ovarian Epithelial Cancer
NCT00011986	Phase 3	COMPLETED	Combination Chemotherapy in Treating Patients With Stage III or Stage IV Ovarian Epithelial Cancer or Primary Peritoneal Cancer
NCT00028743	Phase 3	COMPLETED	Combination Chemotherapy Regimens in Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer
NCT00033605	Phase 3	COMPLETED	Octreotide in Preventing Diarrhea in Patients Who Are Undergoing Radiation Therapy to the Pelvis
NCT00043082	Phase 3	COMPLETED	S0200 Carboplatin With or Without Doxil in Patients With Recurrent Ovarian Cancer
NCT00050375	Phase 3	TERMINATED	Clinical Trial for Ovarian Cancer (OvaRex®)
NCT00052468	Phase 3	COMPLETED	Carboplatin/Paclitaxel +/-Gemcitabine in Treating Patients With Ovarian Epithelial or Fallopian Tube Cancer
NCT00057720	Phase 3	COMPLETED	TLK286 (Telcyta) vs. Doxil/Caelyx or Hycamtin in Platinum Refractory or Resistant Ovarian Cancer
NCT00098878	Phase 3	COMPLETED	Carboplatin in Treating Patients With Stage IC-IV Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
NCT00102375	Phase 3	COMPLETED	Paclitaxel, Carboplatin, and Topotecan in Patients With Ovarian Cancer

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for FANCD2 across ~30M SureChEMBL compounds — explore on Sugi Predict.