FAN1

Chr 15AR

FANCD2 and FANCI associated nuclease 1

Also known as: KIAA1018, KMIN, MTMR15, hFAN1

NCBI Gene: 22909 ENSG00000198690 UniProt: Q9Y2M0 OMIM: 613534

The protein functions as a nuclease that repairs DNA interstrand cross-links through 5' flap endonuclease and 5'-3' exonuclease activity, specifically resolving homologous recombination intermediates at sites of DNA damage. Mutations cause karyomegalic interstitial nephritis, a kidney disease characterized by enlarged nuclei in renal tubular cells, inherited in an autosomal recessive pattern. The gene shows low constraint against loss-of-function variants (LOEUF 1.117), reflecting its recessive inheritance pattern.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

ARLOEUF 1.121 OMIM phenotype

Clinical Summary— FAN1

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Gene-Disease Validity (ClinGen)

hereditary nonpolyposis colon cancer · ADLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

61 unique Pathogenic / Likely Pathogenic· 336 VUS of 625 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — FAN1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

-0.05Z-score

OE missense 1.01 (0.94–1.08)

571 obs / 567.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.86 (0.67–1.12)

0≤0.351.4

Missense OE?1.01 (0.94–1.08)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 42 / 48.6Missense obs/exp: 571 / 567.8Syn Z: -0.89

ClinVar Variant Classifications

625 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22

Likely Pathogenic39

VUS336

Likely Benign137

Benign57

Conflicting17

Pathogenic

Likely Pathogenic

336

VUS

137

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	21	1	0	0	22
Likely Pathogenic	38	1	0	0	39
VUS	3	311	18	4	336
Likely Benign	0	20	35	82	137
Benign	1	2	48	6	57
Conflicting	—				17
Total	63	335	101	92	608

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

View in ClinVar →

179 pathogenic / likely-pathogenic (of 239) ClinVar copy-number / structural variants overlap FAN1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →