FAN1

Chr 15

FANCD2 and FANCI associated nuclease 1

Also known as: KIAA1018, KMIN, MTMR15, hFAN1

NCBI Gene: 22909 ENSG00000198690 UniProt: Q9Y2M0

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 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 ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtInterstitial nephritis, karyomegalic

Clinical highlights

Gene–disease validity (ClinGen)

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.12

LOEUF

—

Mechanism

📖

GeneReview available — FAN1

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Background carrier burden — how many people carry a rare variant somewhere in FAN1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 47

1,348 rare PASS variants

Rare truncating (LoF)

1 in 340

259 rare PASS variants

Rare synonymous (reference)

1 in 57

510 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FAN1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 69	1 in 340
South Asian	~43k	1 in 38	1 in 280
Remaining (unassigned)	~30k	1 in 41	1 in 270
European (Finnish)	~27k	1 in 200	1 in 670
Admixed American	~22k	1 in 46	1 in 380
African / African American	~21k	1 in 28	1 in 460
East Asian	~20k	1 in 45	1 in 270
Ashkenazi Jewish	~13k	1 in 380	1 in 840
Middle Eastern	~2,884	1 in 36	1 in 320

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.