FAN1

Chr 15AR

FANCD2 and FANCI associated nuclease 1

Also known as: KIAA1018, KMIN, MTMR15, hFAN1

NCBI Gene: 22909ENSG00000198690UniProt: Q9Y2M0

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]

Primary Disease Associations & Inheritance

Interstitial nephritis, karyomegalicMIM #614817
AR
853
ClinVar variants
69
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— FAN1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
69 Pathogenic / Likely Pathogenic· 292 VUS of 853 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.12LOEUF
pLI 0.000
Z-score 0.88
OE 0.86 (0.67–1.12)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.05Z-score
OE missense 1.01 (0.94–1.08)
571 obs / 567.8 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.86 (0.67–1.12)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.01 (0.94–1.08)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.08
0≤1.21.6
LoF obs/exp: 42 / 48.6Missense obs/exp: 571 / 567.8Syn Z: -0.89

ClinVar Variant Classifications

853 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38
Likely Pathogenic31
VUS292
Likely Benign68
Benign43
Conflicting11
38
Pathogenic
31
Likely Pathogenic
292
VUS
68
Likely Benign
43
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
0
33
0
38
Likely Pathogenic
16
0
15
0
31
VUS
1
257
30
4
292
Likely Benign
0
10
27
31
68
Benign
1
0
40
2
43
Conflicting
—11
Total2326714537483

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

FAN1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Interstitial nephritis, karyomegalic

MIM #614817

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genetic modifiers of Huntington disease differentially influence motor and cognitive domains.
Lee JM et al.·Am J Hum Genet
2022
FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders.
Deshmukh AL et al.·J Huntingtons Dis
2021Review
Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease highlight shared and tissue-specific effects.
Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium·Nat Genet
2025
Structural and molecular basis of PCNA-activated FAN1 nuclease function in DNA repair.
Li F et al.·Nat Commun
2025
Common variants in FAN1, located in 15q13.3, confer risk for schizophrenia and bipolar disorder in Han Chinese.
Jian X et al.·Prog Neuropsychopharmacol Biol Psychiatry
2020Meta-analysis
Germline Variants in DNA Interstrand-Cross Link Repair Genes May Contribute to Increased Susceptibility for Serrated Polyposis Syndrome.
Silva P et al.·Int J Mol Sci
2024
Modeling of FAN1-Deficient Kidney Disease Using a Human Induced Pluripotent Stem Cell-Derived Kidney Organoid System.
Lim SW et al.·Cells
2023Functional
Therapeutic targeting of mismatch repair proteins in triplet repeat expansion diseases.
Marzec P et al.·DNA Repair (Amst)
2025Review
On the role of FAN1 in Fanconi anemia.
Trujillo JP et al.·Blood
2012
Phenotypic and Genotypic Features of the FAN1 Mutation-Related Disease in a Large Hungarian Family.
Császár I et al.·Int J Mol Sci
2024Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools