FAN1

Summary

FAN1 (FANCD2 and FANCI associated nuclease 1, HGNC:29170) is a protein-coding gene on chromosome 15q13.3, encoding Fanconi-associated nuclease 1 (Q9Y2M0). Nuclease required for the repair of DNA interstrand cross-links (ICL) recruited at sites of DNA damage by monoubiquitinated FANCD2.

This gene plays a role in DNA interstrand cross-link repair and encodes a protein with 5’ flap endonuclease and 5’-3’ exonuclease activity. Mutations in this gene cause karyomegalic interstitial nephritis. Alternatively spliced transcript variants encoding distinct isoforms have been described.

Source: NCBI Gene 22909 — RefSeq curated summary.

At a glance

• Gene–disease (curated): karyomegalic interstitial nephritis (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 601 total — 20 pathogenic, 32 likely-pathogenic
• Phenotypes (HPO): 13
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_014967

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29170
Approved symbol	FAN1
Name	FANCD2 and FANCI associated nuclease 1
Location	15q13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000198690
Ensembl biotype	protein_coding
OMIM	613534
Entrez	22909

Gene structure

Transcript identifiers

Ensembl transcripts: 48 — 31 protein_coding, 11 retained_intron, 5 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000362065, ENST00000561594, ENST00000561607, ENST00000562881, ENST00000562892, ENST00000565280, ENST00000565466, ENST00000568145, ENST00000602886, ENST00000654013, ENST00000654056, ENST00000655421, ENST00000656109, ENST00000656307, ENST00000656435, ENST00000657391, ENST00000658773, ENST00000661974, ENST00000662114, ENST00000664070, ENST00000664837, ENST00000665705, ENST00000665894, ENST00000666143, ENST00000666852, ENST00000667837, ENST00000670074, ENST00000670849, ENST00000879296, ENST00000879297, ENST00000879298, ENST00000879299, ENST00000879300, ENST00000879301, ENST00000915271, ENST00000915272, ENST00000915273, ENST00000915274, ENST00000915275, ENST00000915276, ENST00000915277, ENST00000915278, ENST00000967652, ENST00000967653, ENST00000967654, ENST00000967655, ENST00000967656, ENST00000967657

RefSeq mRNA: 4 — MANE Select: NM_014967 NM_001146094, NM_001146095, NM_001146096, NM_014967

CCDS: CCDS32186, CCDS58344

Canonical transcript exons

ENST00000362065 — 15 exons

Exon	Start	End
ENSE00000881038	30904512	30905897
ENSE00001401786	30903915	30904011
ENSE00001417258	30941566	30943108
ENSE00003467818	30922235	30922354
ENSE00003471464	30913858	30914091
ENSE00003487803	30929203	30929397
ENSE00003500763	30930543	30930671
ENSE00003512496	30925789	30925939
ENSE00003532944	30908118	30908258
ENSE00003560553	30910614	30910815
ENSE00003566369	30925127	30925291
ENSE00003578487	30918164	30918295
ENSE00003610011	30928553	30928656
ENSE00003613148	30920545	30920653
ENSE00003618057	30937119	30937259

Expression profiles

Bgee: expression breadth ubiquitous, 214 present calls, max score 93.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.1459 / max 125.9296, expressed in 1655 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
145648	6.9792	1633
145647	1.0377	661
145646	0.1290	57

Top tissues by expression

247 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	93.51	silver quality
right hemisphere of cerebellum	UBERON:0014890	88.57	gold quality
gastrocnemius	UBERON:0001388	88.48	gold quality
muscle of leg	UBERON:0001383	88.22	gold quality
ventricular zone	UBERON:0003053	88.06	gold quality
cerebellar hemisphere	UBERON:0002245	88.00	gold quality
cerebellar cortex	UBERON:0002129	87.92	gold quality
body of pancreas	UBERON:0001150	87.78	gold quality
ganglionic eminence	UBERON:0004023	87.04	gold quality
cerebellum	UBERON:0002037	86.73	gold quality
hindlimb stylopod muscle	UBERON:0004252	86.20	gold quality
right uterine tube	UBERON:0001302	85.92	gold quality
pancreas	UBERON:0001264	85.60	gold quality
left ovary	UBERON:0002119	85.54	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.46	gold quality
right frontal lobe	UBERON:0002810	85.41	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	85.39	gold quality
right ovary	UBERON:0002118	85.37	gold quality
adrenal tissue	UBERON:0018303	84.95	gold quality
apex of heart	UBERON:0002098	84.66	gold quality
metanephros cortex	UBERON:0010533	84.62	gold quality
skin of abdomen	UBERON:0001416	84.60	gold quality
prefrontal cortex	UBERON:0000451	84.57	gold quality
cortical plate	UBERON:0005343	84.57	gold quality
right lobe of thyroid gland	UBERON:0001119	84.54	gold quality
right adrenal gland	UBERON:0001233	84.53	gold quality
corpus callosum	UBERON:0002336	84.53	gold quality
muscle layer of sigmoid colon	UBERON:0035805	84.53	gold quality
smooth muscle tissue	UBERON:0001135	84.45	gold quality
body of uterus	UBERON:0009853	84.31	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.85

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

92 targeting FAN1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-3681-5P	99.82	66.88	387
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-3680-3P	99.75	72.51	3095

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 37)

• Study describes how a highly conserved protein, KIAA1018/MTMR15/FAN1, that interacts with, and is recruited to sites of DNA damage by, the monoubiquitinated form of FANCD2. (PMID:20603015)
• KIAA1018 is a 5’–>3’ exonuclease and a structure-specific endonuclease that preferentially incises 5’ flaps; like cells from FA patients, human cells depleted of KIAA1018 are sensitized to ICL-inducing agents and display chromosomal instability. (PMID:20603016)
• FAN1 colocalizes at sites of DNA damage with the ID complex in a manner dependent on FAN1’s ubiquitin-binding domain (UBZ), the FANCI-FAND2 (ID) complex, and monoubiquitination of FANCD2. (PMID:20603073)
• study characterizes FANI which promotes DNA interstrand cross-linking repair in a manner strictly dependent on its ability to accumulate at or near sites of DNA damage and that relies on mono-ubiquitylation of the FANCI-FANCD2 complex (PMID:20671156)
• Data show that FAN1 is a nuclear protein and forms DNA-damage-induced foci, which appear to be at stalled replication forks as denoted by RPA colocalization. (PMID:20935496)
• Data show that FAN1 in DT40 cells participates in the processing of damage induced by interstrand cross-linking-generating agents also independently of the classical FA pathway. (PMID:21115814)
• Two FAN1 variants do not appear to be causal for breast cancer. (PMID:21858661)
• Our results suggest that FAN1 has a minor role in interstrand crosslink repair compared with true Fanconi anemia genes and exclude FAN1 as a novel FA gene. (PMID:22611161)
• By exome sequencing, we identified mutations in FAN1 as a cause of karyomegalic interstitial nephritis, a disorder that serves as a model for renal fibrosis. (PMID:22772369)
• FAN1 might be a new mitotic substrate of APC/CCdh1 that plays a key role during mitotic exit. (PMID:22854063)
• FAN1 encodes a DNA repair enzyme, thus implicating abnormalities in DNA repair in the susceptibility to schizophrenia or autism (PMID:24344280)
• Results show that FAN1 utilizes its nuclease activity-in cooperation with the BLM-FANCD2 complex-to promote replication fork restart and simultaneous suppression of new origin firing. (PMID:25135477)
• In this work, FAN1-DNA crystal structures and biochemical data reveal that human FAN1 cleaves DNA successively at every third nucleotide (PMID:25430771)
• The crystal structures of human FAN1 in complex with a 5’ flap DNA substrate show that two FAN1 molecules form a head-to-tail dimer to locate the lesion, orient the DNA, and unwind a 5’ flap for subsequent incision. (PMID:25500724)
• FAN1 efficiently promoted DNA incision at the proper site of RPA-coated 5’-flapped DNA. Therefore, FAN1 possesses the ability to promote the ICL repair of 5’-flapped DNA covered by RPA. (PMID:25922199)
• Detected FAN1 mutations in approximately 3% of families who met the Amsterdam criteria for hereditary colorectal cancer and had mismatch repair-proficient cancers with no previously associated mutations. (PMID:26052075)
• EXO1 and FEN1 cleaved the substrate at the boundary between the single-stranded 5’ flap and the duplex, whereas FAN1 incised it three to four nucleotides in the double-stranded region. (PMID:26221031)
• show that DNA repair genes (fan1 and pms2) significantly modify age at onset in Huntington’s Disease and Spinocerebellar Ataxias, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats (PMID:27044000)
• The structures, function, and proposed mechanisms of FAN1 nuclease are discussed, and the insights into its role in interstrand cross-links repair and in processing of stalled replication forks are provided. [REVIEW] (PMID:28623094)
• FAN1 interaction with ubiquitylated PCNA alleviates replication stress and preserves genomic integrity independently of BRCA2 (PMID:29051491)
• hFAN1 homodimerization plays a role in biological processes that involve 5’ DNA Flap cleavage. (PMID:29518739)
• We show that FAN1 binds to the expanded HTT CAG repeat DNA and its nuclease activity is not required for protection against CAG repeat expansion. These data shed new mechanistic insights into how the genetic modifiers of Huntington’s disease (HD) act to alter disease progression and show that FAN1 affects somatic expansion of the CAG repeat through a nuclease-independent mechanism. (PMID:30358836)
• The results of our study argue against the implication of pathogenic variants of FAN1 in unexplained cases of suspected genetic predisposition to colorectal polyps/cancer. (PMID:30639725)
• Variation in DNA Repair System Gene as an Additional Modifier of Age at Onset in Spinocerebellar Ataxia Type 3/Machado-Joseph Disease. (PMID:31587151)
• Common variants in FAN1, located in 15q13.3, confer risk for schizophrenia and bipolar disorder in Han Chinese. (PMID:32450113)
• Genetic and Functional Analyses Point to FAN1 as the Source of Multiple Huntington Disease Modifier Effects. (PMID:32589923)
• FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders. (PMID:33579867)
• New familial cases of karyomegalic interstitial nephritis with mutations in the FAN1 gene. (PMID:34126972)
• FANCD2-Associated Nuclease 1 Partially Compensates for the Lack of Exonuclease 1 in Mismatch Repair. (PMID:34228493)
• FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington’s disease. (PMID:34469738)
• FAN1 exo- not endo-nuclease pausing on disease-associated slipped-DNA repeats: A mechanism of repeat instability. (PMID:34879276)
• New insights on familial colorectal cancer type X syndrome. (PMID:35181726)
• Exome sequencing of individuals with Huntington’s disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset. (PMID:35379994)
• Persistent DNA damage underlies tubular cell polyploidization and progression to chronic kidney disease in kidneys deficient in the DNA repair protein FAN1. (PMID:35931300)
• FAN1 removes triplet repeat extrusions via a PCNA- and RFC-dependent mechanism. (PMID:37549289)
• Posttranscriptional regulation of FAN1 by miR-124-3p at rs3512 underlies onset-delaying genetic modification in Huntington’s disease. (PMID:38607933)
• Phenotypic and Genotypic Features of the FAN1 Mutation-Related Disease in a Large Hungarian Family. (PMID:38892095)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	fan1	ENSDARG00000062269
mus_musculus	Fan1	ENSMUSG00000033458
rattus_norvegicus	Fan1	ENSRNOG00000023985
caenorhabditis_elegans		WBGENE00015310

Protein

Protein identifiers

Fanconi-associated nuclease 1 — Q9Y2M0 (reviewed: Q9Y2M0)

Alternative names: FANCD2/FANCI-associated nuclease 1, Myotubularin-related protein 15

All UniProt accessions (8): A0A590UJ38, A0A590UJF5, A0A590UJL5, A0A590UK78, A0A590UKC0, Q9Y2M0, H3BQ24, H3BUK3

UniProt curated annotations — full annotation on UniProt →

Function. Nuclease required for the repair of DNA interstrand cross-links (ICL) recruited at sites of DNA damage by monoubiquitinated FANCD2. Specifically involved in repair of ICL-induced DNA breaks by being required for efficient homologous recombination, probably in the resolution of homologous recombination intermediates. Not involved in DNA double-strand breaks resection. Acts as a 5’-3’ exonuclease that anchors at a cut end of DNA and cleaves DNA successively at every third nucleotide, allowing to excise an ICL from one strand through flanking incisions. Probably keeps excising with 3’-flap annealing until it reaches and unhooks the ICL. Acts at sites that have a 5’-terminal phosphate anchor at a nick or a 1- or 2-nucleotide flap and is augmented by a 3’ flap. Also has endonuclease activity toward 5’-flaps.

Subunit / interactions. Interacts with FANCD2 (when monoubiquitinated). Interacts with FANCI, MLH1, MLH3 and PMS2.

Subcellular location. Nucleus.

Post-translational modifications. Ubiquitinated and degraded during mitotic exit by the APC/C-Cdh1 complex.

Disease relevance. Interstitial nephritis, karyomegalic (KMIN) [MIM:614817] A rare kidney disease characterized by chronic tubulointerstitial nephritis associated with massively enlarged tubular epithelial cell nuclei. The clinical picture is associated with recurrent upper respiratory tract infections in addition to chronic kidney disease beginning in the third decade of life. The disease is caused by variants affecting the gene represented in this entry. Schizophrenia and autism. Schizophrenia is a severe psychiatric disorder characterized by positive, negative, and cognitive symptoms, and it is associated with increased mortality and severely reduced fecundity. Autim is a complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Most individuals with autism also manifest moderate intellectual disability. Disease susceptibility may be associated with variants affecting the gene represented in this entry.

Cofactor. Binds 2 magnesium or manganese ions per subunit.

Domain organisation. The UBZ4-type zinc finger specifically binds monoubiquitinated FANCD2. The KEN box and D-box are required for interaction with FZR1/CDH1 and essential for APC(CDH1)-mediated ubiquitination.

Similarity. Belongs to the FAN1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y2M0-1	1	yes
Q9Y2M0-2	2

RefSeq proteins (4): NP_001139566, NP_001139567, NP_001139568, NP_055782* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006642	Rad18_UBZ4	Domain
IPR011856	tRNA_endonuc-like_dom_sf	Homologous_superfamily
IPR014883	VRR_NUC	Domain
IPR033315	Fan1-like	Family
IPR049125	FAN1-like_WH	Domain
IPR049126	FAN1-like_TPR	Domain
IPR049132	FAN1-like_euk	Family
IPR049138	Fan1_SAP_met	Domain

Pfam: PF08774, PF21169, PF21170, PF21315

UniProt features (105 total): helix 37, strand 19, mutagenesis site 10, binding site 9, turn 7, sequence variant 5, compositionally biased region 3, region of interest 3, sequence conflict 3, splice variant 2, short sequence motif 2, chain 1, domain 1, zinc finger region 1, modified residue 1, coiled-coil region 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
4REC	X-RAY DIFFRACTION	2.2
8S5A	X-RAY DIFFRACTION	2.65
4RIC	X-RAY DIFFRACTION	2.8
4RY3	X-RAY DIFFRACTION	2.8
4RI8	X-RAY DIFFRACTION	2.9
4RI9	X-RAY DIFFRACTION	2.9
4RIA	X-RAY DIFFRACTION	3
9EO1	ELECTRON MICROSCOPY	3.2
4RIB	X-RAY DIFFRACTION	3.25
9EOA	ELECTRON MICROSCOPY	3.27
4RID	X-RAY DIFFRACTION	3.3
9CG4	ELECTRON MICROSCOPY	3.37
9GY0	ELECTRON MICROSCOPY	3.42
9CHM	ELECTRON MICROSCOPY	3.47
4REA	X-RAY DIFFRACTION	3.81
9CL7	ELECTRON MICROSCOPY	3.83
9CMA	ELECTRON MICROSCOPY	3.97
4REB	X-RAY DIFFRACTION	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2M0-F1	70.71	0.48

Functional residue map

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

Ligand- & substrate-binding residues (9): 44; 47; 59; 64; 834; 960; 960; 975; 976

Post-translational modifications (1): 180

Mutagenesis-validated functional residues (10):

Position	Phenotype
44	abolishes interaction with monoubiquitinated fancd2; when associated with a-47.
47	abolishes interaction with monoubiquitinated fancd2; when associated with a-44.
477	still localized to sites of dna damage but the strength of the signal is diminished.
706	strongly reduced affinity for sites that have a 5’-terminal phosphate anchor at a flap of 1 nucleotide; when associated
864	loss of nuclease activity; when associated with a-960; a-975 and a-977.
952	strongly reduced affinity for sites that have a 5’-terminal phosphate anchor at a flap of 1 nucleotide; when associated
960	loss of nuclease activity. loss of nuclease activity; when associated with a-864; a-975 and a-977.
975	loss of nuclease activity; when associated with a-864; a-960 and a-977.
977	loss of nuclease activity; when associated with a-864; a-960 and a-975.
981–982	loss of nuclease activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6783310	Fanconi Anemia Pathway

MSigDB gene sets: 150 (showing top): PID_FANCONI_PATHWAY, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GCM_MAP4K4, GOMF_ENDONUCLEASE_ACTIVITY, GCM_GSPT1, GOMF_NUCLEASE_ACTIVITY, chr15q13, MODULE_331, GOBP_NUCLEOTIDE_EXCISION_REPAIR, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_DN, GOBP_DNA_DAMAGE_RESPONSE, GOBP_INTERSTRAND_CROSS_LINK_REPAIR, REACTOME_FANCONI_ANEMIA_PATHWAY, GCM_NF2, REACTOME_DNA_REPAIR

GO Biological Process (5): double-strand break repair via homologous recombination (GO:0000724), DNA repair (GO:0006281), nucleotide-excision repair (GO:0006289), interstrand cross-link repair (GO:0036297), DNA damage response (GO:0006974)

GO Molecular Function (16): magnesium ion binding (GO:0000287), phosphodiesterase I activity (GO:0004528), zinc ion binding (GO:0008270), 5’-3’ exonuclease activity (GO:0008409), 5’-flap endonuclease activity (GO:0017108), flap-structured DNA binding (GO:0070336), ubiquitin-modified protein reader activity (GO:0140036), nucleic acid binding (GO:0003676), DNA binding (GO:0003677), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), exonuclease activity (GO:0004527), protein binding (GO:0005515), hydrolase activity (GO:0016787), hydrolase activity, acting on ester bonds (GO:0016788), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), cilium (GO:0005929), intercellular bridge (GO:0045171)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
DNA Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
DNA repair	2
exonuclease activity	2
binding	2
nuclease activity	2
recombinational repair	1
double-strand break repair	1
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
metal ion binding	1
phosphoric diester hydrolase activity	1
transition metal ion binding	1
DNA endonuclease activity, producing 5’-phosphomonoesters	1
flap endonuclease activity	1
DNA binding	1
ubiquitin-like protein reader activity	1
nucleic acid binding	1
catalytic activity, acting on a nucleic acid	1
hydrolase activity, acting on ester bonds	1
catalytic activity	1
hydrolase activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

658 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FAN1	FANCI	Q9NVI1	982
FAN1	FANCD2	Q9BXW9	981
FAN1	MTMR10	Q9NXD2	949
FAN1	TRPM1	Q7Z4N2	852
FAN1	MLH1	P40692	844
FAN1	PMS1	P54277	827
FAN1	RAD18	Q9NS91	750
FAN1	SLX4	Q8IY92	721
FAN1	SLX1A	Q9BQ83	690
FAN1	PMS2	P54278	679
FAN1	IFT80	Q9P2H3	650
FAN1	FANCM	Q8IYD8	649
FAN1	DCLRE1A	Q6PJP8	640
FAN1	OTUD7A	Q8TE49	620
FAN1	MUS81	Q96NY9	607

IntAct

8 interactions, top by confidence:

A	B	Type	Score
MLH1	PMS1	psi-mi:“MI:0914”(association)	0.830
FAN1	CCR1	psi-mi:“MI:0915”(physical association)	0.370
FAN1		psi-mi:“MI:0914”(association)	0.350
FSCN1	FANCG	psi-mi:“MI:0914”(association)	0.350
FSCN1	UBB	psi-mi:“MI:0914”(association)	0.350
MLH1	GLI2	psi-mi:“MI:0914”(association)	0.350
DSCR9	FAN1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (115): FAN1 (Affinity Capture-Western), FAN1 (Affinity Capture-Western), UBC (Affinity Capture-MS), FAN1 (Reconstituted Complex), UBC (Reconstituted Complex), AP2A2 (Affinity Capture-MS), ANXA7 (Affinity Capture-MS), HEXA (Affinity Capture-MS), MLH1 (Affinity Capture-MS), PIK3C2B (Affinity Capture-MS), PMS1 (Affinity Capture-MS), PMS2 (Affinity Capture-MS), PPP2R1A (Affinity Capture-MS), PSMD11 (Affinity Capture-MS), SUPT5H (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8GLK3, A0A974CYQ5, A2AHJ4, A5WW08, D2HNY3, D2HWM5, E7F6T8, F1ND48, O15040, O70260, O95071, P59328, Q3TLR7, Q4V837, Q58DC2, Q58WW2, Q5E9J6, Q5F479, Q5FWP4, Q5NVC7, Q5R9B8, Q5RF77, Q5RGA4, Q5RHI5, Q5ZLG9, Q62671, Q66JG1, Q6DDH2, Q6P1W0, Q6P256, Q6PCD5, Q6PJI9, Q6RI45, Q80TP3, Q80U93, Q810L3, Q8C0M0, Q8CBW4, Q8CIK8, Q8CIN9

Diamond homologs: D2HNY3, P90740, Q1LWH4, Q55FW8, Q5SNL7, Q5XVJ4, Q69ZT1, Q9I2N0, Q9Y2M0, A8WZU5, Q9Y804

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	32
Uncertain significance	324
Likely benign	121
Benign	51

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1179198	NM_014967.5(FAN1):c.1702C>T (p.Gln568Ter)	Pathogenic
1344663	NM_014967.5(FAN1):c.2590C>T (p.Gln864Ter)	Pathogenic
1947897	NM_014967.5(FAN1):c.289del (p.Asp96_Val97insTer)	Pathogenic
2123202	NM_014967.5(FAN1):c.1958dup (p.Leu653fs)	Pathogenic
2706852	NM_014967.5(FAN1):c.972_973del (p.His324fs)	Pathogenic
2854037	NM_014967.5(FAN1):c.299dup (p.Lys101fs)	Pathogenic
3248651	NM_014967.5(FAN1):c.1369C>T (p.Gln457Ter)	Pathogenic
3376569	NM_014967.5(FAN1):c.322_323del (p.Asn108fs)	Pathogenic
37094	NM_014967.5(FAN1):c.2120G>A (p.Trp707Ter)	Pathogenic
37095	NM_014967.5(FAN1):c.1234+2T>A	Pathogenic
37096	NM_014967.5(FAN1):c.2036_2037del (p.Arg679fs)	Pathogenic
37097	NM_014967.5(FAN1):c.2245C>T (p.Arg749Ter)	Pathogenic
37101	NM_014967.5(FAN1):c.2809G>C (p.Gly937Arg)	Pathogenic
3721634	NM_014967.5(FAN1):c.1606C>T (p.Arg536Ter)	Pathogenic
3775318	NM_014967.5(FAN1):c.1987_1996del (p.Gly663fs)	Pathogenic
4022075	NM_014967.5(FAN1):c.2241del (p.Gln748fs)	Pathogenic
4277813	NM_014967.5(FAN1):c.1480C>T (p.Gln494Ter)	Pathogenic
437428	NM_014967.5(FAN1):c.1102C>T (p.Gln368Ter)	Pathogenic
437429	NM_014967.5(FAN1):c.2616del (p.Asp873fs)	Pathogenic
973638	NM_014967.5(FAN1):c.256_257del (p.Met86fs)	Pathogenic
1179186	NM_014967.5(FAN1):c.332del (p.Pro111fs)	Likely pathogenic
3345497	NM_014967.5(FAN1):c.2802C>A (p.Cys934Ter)	Likely pathogenic
3349090	NM_014967.5(FAN1):c.433del (p.Arg145fs)	Likely pathogenic
3350994	NM_014967.5(FAN1):c.929C>G (p.Ser310Ter)	Likely pathogenic
3576948	NM_014967.5(FAN1):c.28A>T (p.Lys10Ter)	Likely pathogenic
3576949	NM_014967.5(FAN1):c.31_34del (p.Lys11fs)	Likely pathogenic
3576950	NM_014967.5(FAN1):c.32_35del (p.Lys11fs)	Likely pathogenic
3576962	NM_014967.5(FAN1):c.346dup (p.Ser116fs)	Likely pathogenic
3576977	NM_014967.5(FAN1):c.652del (p.Cys218fs)	Likely pathogenic
3576982	NM_014967.5(FAN1):c.791dup (p.Leu264fs)	Likely pathogenic

SpliceAI

3276 predictions. Top by Δscore:

Variant	Effect	Δscore
15:30905868:G:T	donor_gain	1.0000
15:30908116:A:AG	acceptor_gain	1.0000
15:30908117:G:GG	acceptor_gain	1.0000
15:30908117:GCT:G	acceptor_gain	1.0000
15:30908117:GCTA:G	acceptor_gain	1.0000
15:30910603:A:AG	acceptor_gain	1.0000
15:30910604:A:G	acceptor_gain	1.0000
15:30910608:TTTCA:T	acceptor_loss	1.0000
15:30910609:TTCAG:T	acceptor_loss	1.0000
15:30910610:TCAG:T	acceptor_loss	1.0000
15:30910611:CAG:C	acceptor_loss	1.0000
15:30910612:A:AG	acceptor_gain	1.0000
15:30910613:G:GG	acceptor_gain	1.0000
15:30910613:GA:G	acceptor_gain	1.0000
15:30910613:GAA:G	acceptor_gain	1.0000
15:30910613:GAAT:G	acceptor_gain	1.0000
15:30910613:GAATC:G	acceptor_gain	1.0000
15:30910801:A:AG	donor_gain	1.0000
15:30910802:G:GG	donor_gain	1.0000
15:30913856:A:AG	acceptor_gain	1.0000
15:30913857:G:GG	acceptor_gain	1.0000
15:30913857:GA:G	acceptor_gain	1.0000
15:30914091:GGTA:G	donor_loss	1.0000
15:30914092:G:GG	donor_gain	1.0000
15:30914092:GTAAG:G	donor_loss	1.0000
15:30914093:T:A	donor_loss	1.0000
15:30922362:G:GG	donor_gain	1.0000
15:30925298:A:T	donor_gain	1.0000
15:30925938:GG:G	donor_gain	1.0000
15:30925939:GG:G	donor_gain	1.0000

AlphaMissense

6699 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:30908165:T:A	W428R	0.996
15:30908165:T:C	W428R	0.996
15:30930645:T:A	W964R	0.996
15:30930645:T:C	W964R	0.996
15:30908153:C:A	R424S	0.995
15:30930631:C:A	P959H	0.995
15:30937163:G:C	Q987H	0.995
15:30937163:G:T	Q987H	0.995
15:30937132:A:T	K977I	0.994
15:30937133:A:C	K977N	0.994
15:30937133:A:T	K977N	0.994
15:30908154:G:C	R424P	0.993
15:30925840:T:C	F797L	0.993
15:30925842:T:A	F797L	0.993
15:30925842:T:G	F797L	0.993
15:30925895:A:T	E815V	0.992
15:30914085:T:C	L602P	0.991
15:30922311:G:C	R710P	0.991
15:30910668:T:C	L477P	0.990
15:30930647:G:C	W964C	0.990
15:30930647:G:T	W964C	0.990
15:30908145:T:C	L421P	0.989
15:30922238:G:C	A686P	0.989
15:30930547:T:C	L931P	0.989
15:30937144:A:C	D981A	0.989
15:30937214:C:G	C1004W	0.989
15:30908143:G:C	R420S	0.988
15:30908143:G:T	R420S	0.988
15:30929375:T:C	F922S	0.988
15:30937144:A:T	D981V	0.988

dbSNP variants (sampled 300 via entrez): RS1000010016 (15:30917016 G>A,C), RS1000066150 (15:30909990 G>T), RS1000075975 (15:30909803 C>T), RS1000097187 (15:30942193 T>C), RS1000206605 (15:30936978 C>T), RS1000431078 (15:30925540 C>T), RS1000470809 (15:30935043 C>A,T), RS1000472771 (15:30936915 C>T), RS1000487265 (15:30932775 G>A), RS1000517937 (15:30932551 G>A,C), RS1000544054 (15:30935423 T>C), RS1000641035 (15:30936492 T>A), RS1000697246 (15:30928090 T>C), RS1000919264 (15:30904008 C>T), RS1000952816 (15:30907555 CAAAA>C,CAAA,CAAAAA)

Disease associations

OMIM: gene MIM:613534 | disease phenotypes: MIM:614817

GenCC curated gene-disease

Disease	Classification	Inheritance
karyomegalic interstitial nephritis	Definitive	Autosomal recessive
Lynch syndrome	Supportive	Autosomal dominant
hereditary nonpolyposis colon cancer	Limited	Unknown

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
karyomegalic interstitial nephritis	Definitive	AR
hereditary nonpolyposis colon cancer	Limited	AD

Mondo (5): karyomegalic interstitial nephritis (MONDO:0013898), hereditary breast ovarian cancer syndrome (MONDO:0003582), kidney failure (MONDO:0001106), hereditary nonpolyposis colon cancer (MONDO:0018630), Lynch syndrome (MONDO:0005835)

Orphanet (2): Karyomegalic interstitial nephritis (Orphanet:401996), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000090	Nephronophthisis
HP:0000093	Proteinuria
HP:0000790	Hematuria
HP:0001970	Tubulointerstitial nephritis
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003076	Glycosuria
HP:0003138	Increased blood urea nitrogen
HP:0003259	Elevated circulating creatinine concentration
HP:0003676	Progressive
HP:0003774	Stage 5 chronic kidney disease
HP:0032948	Renal interstitial fibrosis
HP:0041050	Renal tubular cyst

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001905_9	Hypertriglyceridemia	6.000000e-06
GCST004691_16	Huntington’s disease progression	8.000000e-06
GCST007113_2	Huntington’s disease (age at onset)	2.000000e-20

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0008336	disease progression measurement
EFO:0004847	age at onset

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D051437	Renal Insufficiency	C12.050.351.968.419.780; C12.200.777.419.780; C12.950.419.780

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	decreases expression	2
Mitomycin	increases response to substance, decreases response to substance	2
GSK-J4	decreases expression	1
FR900359	decreases phosphorylation	1
bufotalin	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
arsenite	increases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Cisplatin	decreases response to substance	1
Clozapine	increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Indomethacin	decreases expression, affects cotreatment	1
Plant Extracts	affects cotreatment, increases expression	1
Quercetin	increases expression	1
Selenium	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	affects expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1

Cellosaurus cell lines

3 cell lines: 1 transformed cell line, 1 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D9EN	Ubigene HEK293 FAN1 KO	Transformed cell line	Female
CVCL_E1WY	HAP1 FAN1 (-)	Cancer cell line	Male
CVCL_ZX45	CMCi001-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

402 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00123331	PHASE4	COMPLETED	Rapamycin Use in Calcineurin Inhibitor (CNI)-Free Immunosuppression for Stabilization/Improvement of Renal Function After Heart Transplantation
NCT00123461	PHASE4	COMPLETED	Study of Safety and Efficacy of Doxercalciferol in Patients With Chronic Kidney Disease, Stage 3 or 4, and Secondary Hyperparathyroidism
NCT00144118	PHASE4	TERMINATED	The Effect of Isoflurane or Sevoflurane on Kidney Function
NCT00184769	PHASE4	COMPLETED	Growth Hormone Treatment in Infants Aged 1 to 2 Years With Chronic Renal Insufficiency (CRI) and Growth Retardation.
NCT00186329	PHASE4	COMPLETED	BNP for Cardio-Renal Decompensation Syndrome (BNP-CARDS)
NCT00194883	PHASE4	SUSPENDED	Effect of Cytokines on Growth of Children With Chronic Kidney Failure
NCT00195429	PHASE4	COMPLETED	A Study Comparing the Withdrawal of Steroids or Tacrolimus in Kidney Transplant Recipients
NCT00195468	PHASE4	COMPLETED	Study Comparing Cyclosporine Dose Reduction vs. Cyclosporine Elimination in Kidney Transplant Recipients Taking Sirolimus
NCT00195481	PHASE4	COMPLETED	Study Evaluating Sirolimus in Kidney Transplant Recipients in India
NCT00209417	PHASE4	TERMINATED	Renal Effects of Two Iodinated Contrast Media in Patients at Risk Undergoing Computed Tomography
NCT00246129	PHASE4	COMPLETED	CamTac Trial:Campath-Tacrolimus vs IL2R MoAb/Tacrolimus/MMF in Renal Transplantation
NCT00247325	PHASE4	COMPLETED	RECOVER:Comparison of Renal Toxicity Between Visipaque(Iodixanol)and Hexabrix(Ioxaglate)in Renal Insufficiency Undergoing Coronary Angiography
NCT00254709	PHASE4	COMPLETED	Study Evaluating Two Different Sirolimus-based Immunosuppressive Regimens in Elderly Kidney Transplant Recipients
NCT00259441	PHASE4	COMPLETED	PROMISS: Simvastatin Prevents the Contrast Induced Acute Renal Failure in Patients With Renal Insufficiency Undergoing Coronary Angiography
NCT00261820	PHASE4	COMPLETED	Study Comparing Two Immunosuppressive Regimens in De Novo Renal Allograft Recipients
NCT00266123	PHASE4	COMPLETED	Study Comparing Two Sirolimus Regimens vs. Tacrolimus and Mycophenolate Mofetil Regimen in Kidney Transplant Recipients
NCT00282217	PHASE4	COMPLETED	Study Evaluating Sirolimus in the Treatment of Kidney Transplant
NCT00294866	PHASE4	COMPLETED	Effect of Paricalcitol on Markers of Inflammation in Hemodialysis Patients
NCT00295555	PHASE4	COMPLETED	Doxazosin Effects on ABPM in Hypertensive Patients With Diabetic Nephropathy
NCT00356954	PHASE4	COMPLETED	NASPI: N-Acetylcysteine vs. Ascorbic Acid for Prevention of Contrast Induced Nephropathy in Renal Insufficiency Undergoing Coronary Catheterization
NCT00368901	PHASE4	COMPLETED	STAAR-2 Clinical Study
NCT00369382	PHASE4	COMPLETED	Study Of The Safety And Efficacy Of Conversion From A CNI To Sirolimus In Renally-Impaired Heart Transplant Recipients
NCT00369733	PHASE4	COMPLETED	STAAR-3 Clinical Study
NCT00369772	PHASE4	COMPLETED	STAAR-1 Clinical Study
NCT00396435	PHASE4	COMPLETED	Correction of Anaemia and Progression of Renal Failure on Transplanted Patients
NCT00412802	PHASE4	COMPLETED	Adaptation Dose of Enoxaparin in Moderate Renal Failure Patients With Acute Coronary Syndrome
NCT00483275	PHASE4	WITHDRAWN	Fall Prevention by Alfacalcidol and Training
NCT00492518	PHASE4	COMPLETED	Acetylcysteine, Theophylline, and a Combination of Both in the Prophylaxis of Contrast-Induced Nephropathy
NCT00495365	PHASE4	TERMINATED	A Dose Conversion Study of Epoetin Alfa in Subjects With the Anemia of Chronic Kidney Disease.
NCT00527059	PHASE4	UNKNOWN	Renal Effects of Levosimendan in Patients Admitted With Acute Decompensated Heart Failure
NCT00566033	PHASE4	COMPLETED	Multiple Intervention and AUdit in Renal Diseases to Optimize Care
NCT00584350	PHASE4	UNKNOWN	Prevention of Contrast Nephropathy During Diagnostic Coronary Angiogram or PCI With Hydratation Based on LEVDP
NCT00613964	PHASE4	TERMINATED	The Effects of Carperitide on Short and Long-term Prognosis in Patients With Both Cardiac and Renal Failure
NCT00650845	PHASE4	COMPLETED	Renal Safety Evaluation After Dotarem®-Enhanced MRI
NCT00656266	PHASE4	TERMINATED	Trial of Calcineurin Inhibitor-Sparing Immunosuppression Regimen in Pediatric Liver Transplantation
NCT00716573	PHASE4	COMPLETED	Efficacy Study of Everolimus on Renal Function in Heart Transplant Recipients With Established Chronic Renal Failure
NCT00748072	PHASE4	COMPLETED	1-deamino 8-d-arginine Vasopressin (DDAVP) in Percutaneous Ultrasound-guided Renal Biopsy
NCT00748904	PHASE4	WITHDRAWN	Rifaximin Versus Lactulose in Renal Failure
NCT00823628	PHASE4	COMPLETED	Contrast-medium Induced Nephrotoxicity in Patients Undergoing Coronary Angiography - Iodixanol Versus Iopromide