FAN1

protein-coding

FANCD2 and FANCI associated nuclease 1

Gene summary

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. [provided by RefSeq, Feb 2016]

Previous symbols:

KIAA1018
MTMR15

MANE transcript

NM_014967.5

Inheritance

ClinVar variants

P:75U:294B:118

Top phenotype

Interstitial nephritis, karyomegalic

gnomAD constraint

pLI —, LoF o/e 0.86

Max pathogenic AF

—

Genomic locus

chr15:30,890,559-30,943,108

External References & Databases

Ensembl (ENSG00000198690)

Transcript & Mutation Effects

hg38 • Region Span ~52.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary nonpolyposis colon cancerLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0018630

Submitter: ClinGen

karyomegalic interstitial nephritisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013898

Submitter: Ambry Genetics

karyomegalic interstitial nephritisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013898

Submitter: ClinGen

*FAN1* (OMIM: 613534), encodes FANCD2/FANCI-associated nuclease 1, a structure-specific endonuclease in the DNA damage response required for the repair of DNA interstrand cross-links (ICLs) (PMID: 20603016). The curated disease entity is autosomal recessive *FAN1*-related karyomegalic interstitial nephritis (KIN; OMIM: 614817; MONDO:0013898), characterized by chronic tubulointerstitial nephropathy with tubular karyomegaly and progressive CKD that frequently progresses to kidney failure. The molecular mechanism is biallelic loss of function, with some pathogenic missense variants also reported (PMID: 22772369). At least 38 distinct likely pathogenic/pathogenic *FAN1* variants have been identified, the majority being protein-truncating (nonsense, frameshift, and canonical splice-site) variants (PMID: 41565023). The gene–disease relationship is supported by genetic evidence (12/12 points; maximum score reached). The initial discovery study identified biallelic *FAN1* variants across 9 families with KIN, establishing *FAN1* as the causal gene (PMID: 22772369). Subsequent independent reports expanded the allelic and phenotypic spectrum across diverse ancestries, including a recurrent founder variant p.Trp707Ter in French Polynesian families (PMID: 34386670), c.1673dup (p.Met558IlefsTer4) in a large Hungarian family (PMID: 38892095), and a homozygous nonsense allele c.2260C>T (p.Arg754Ter) in a biopsy-confirmed multisystem case (PMID: 39294548). A comprehensive natural-history study identified 86 affected families (122 individuals) from 22 countries, with 56 genetically confirmed KIN-*FAN1* families carrying 38 distinct variants, a median age at kidney failure of 45 years, and frequent extra-renal involvement including liver test abnormalities (46%) and pulmonary complications (39%) (PMID: 41565023). The relationship is also supported by experimental evidence (6/6 points). Biochemical and expression studies confirm FAN1's role in ICL repair and its high expression in kidney tissue relative to other organs (PMID: 22772369). Functional alteration studies in patient-derived fibroblasts demonstrate hypersensitivity to the ICL-inducing agent mitomycin C, and truncating variants abolish FAN1 protein expression on Western blot (PMID: 22772369). Non-human model organism data from *Fan1* nuclease-defective knock-in mice and knockout models recapitulate KIN-like renal pathology with tubular karyomegaly, polyploidy, and DNA damage sensitivity (PMIDs: 26980188, 26980189, 27026368). In summary, there is Definitive evidence supporting the relationship between *FAN1* and autosomal recessive karyomegalic interstitial nephritis, with a total score of 18/18 points (genetic evidence 12/12; experimental evidence 6/6). This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on March 11, 2026 (SOP version 12).

karyomegalic interstitial nephritisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013898

Submitter: Orphanet

karyomegalic interstitial nephritisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013898

Submitter: Labcorp Genetics (formerly Invitae)

karyomegalic interstitial nephritisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013898

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Interstitial nephritis, karyomegalicAR

Manifestation: Gastrointestinal; Renal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Individuals may suffer renal failure, and renal transplant has been described

Refs: 7847351; 8546134; 16678356; 17304531; 22772369

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FAN1 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 250

Karyomegalic interstitial nephritisTotal: 211

Inborn genetic diseasesTotal: 151

FAN1-related disorderTotal: 62

not specifiedTotal: 28

FAN1-related disordersTotal: 7

Hereditary breast ovarian cancer syndromeTotal: 2

Kidney failureTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014967.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	85 clinvar	3 clinvar	94
missense	1 clinvar	3 clinvar	284 clinvar	28 clinvar	1 clinvar	317
nonsense	8 clinvar	19 clinvar				27
start loss			1 clinvar			1
frameshift	12 clinvar	27 clinvar	3 clinvar			42
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar			1 clinvar	6
Total	22	53	294	113	5	487

Highest pathogenic variant AF is 0.00011896972

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 92 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014967.5	RefSeq	NP_055782.3	13	MANE Select
ENST00000362065.9	Ensembl	ENSP00000354497.4	13	MANE Select
NM_001146094.2	RefSeq	NP_001139566.1	3	Standard
NM_001146095.1	RefSeq	NP_001139567.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fanconi anemia pathway - Homo sapiens (human)
Fanconi Anemia Pathway
DNA Repair
Fanconi anemia pathway

Biological Process

double-strand break repair via homologous recombination
DNA repair
nucleotide-excision repair
nucleotide-excision repair, DNA incision
interstrand cross-link repair

Molecular Function

magnesium ion binding
phosphodiesterase I activity
protein binding
5'-3' exonuclease activity
5'-flap endonuclease activity

Cellular Component

nucleus
nucleoplasm
cytosol
intercellular bridge

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000362065
Coding exons: 13
Length: 39257
Individuals with no LoFs: 125429
Homozygous LoFs: 0
Heterozygous LoFs: 319
Defined: 125748
p: 0.00127

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0474	571	568	1.01	0.0000316	6675
Missense (PolyPhen)		173	184.99	0.93519		2190
Synonymous	-0.889	235	218	1.08	0.0000125	1959
Loss of Function	0.881	42	48.6	0.864	0.00000276	568

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00087	0.00086	rare
Latino/Admixed American	0.0013	0.0012	notable
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.0022	0.0022	notable
Finnish	0.00079	0.00079	rare
European (Non-Finnish)	0.0013	0.0013	notable
South Asian	0.0017	0.0016	notable
Other	0.0011	0.0011	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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 (PubMed:20603015, PubMed:20603016, PubMed:20603073, PubMed:20671156, PubMed:24981866, PubMed:25430771). Not involved in DNA double-strand breaks resection (PubMed:20603015, PubMed:20603016). 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 (PubMed:25430771). 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 (PubMed:25430771). Also has endonuclease activity toward 5'-flaps (PubMed:20603015, PubMed:20603016, PubMed:24981866). {ECO:0000269|PubMed:20603015, ECO:0000269|PubMed:20603016, ECO:0000269|PubMed:20603073, ECO:0000269|PubMed:20671156, ECO:0000269|PubMed:24981866, ECO:0000269|PubMed:25135477, ECO:0000269|PubMed:25430771}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:22772369}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=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 mental retardation.Disease susceptibility may be associated with variations affecting the gene represented in this entry. {ECO:0000269|PubMed:24344280}.;

Recessive Scores

pRec: 0.0867

Intolerance Scores

RVIS EVS: 0.28
RVIS percentile EVS: 70.76

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium