FEN1

Chr 11

flap structure-specific endonuclease 1

Also known as: FEN-1, MF1, RAD2

NCBI Gene: 2237 ENSG00000168496 UniProt: P39748

The FEN1 protein is a structure-specific nuclease that removes 5'-overhanging flaps during DNA replication and repair, including processing Okazaki fragments and participating in base excision repair. Mutations cause autosomal recessive systemic lupus erythematosus with severe immunodeficiency. This gene is highly intolerant to loss-of-function variants (pLI near 0), suggesting that complete protein loss is likely incompatible with normal development.

ResearchSummary from RefSeq, UniProt

The protein encoded by this gene removes 5' overhanging flaps in DNA repair and processes the 5' ends of Okazaki fragments in lagging strand DNA synthesis. Direct physical interaction between this protein and AP endonuclease 1 during long-patch base excision repair provides coordinated loading of the proteins onto the substrate, thus passing the substrate from one enzyme to another. The protein is a member of the XPG/RAD2 endonuclease family and is one of ten proteins essential for cell-free DNA replication. DNA secondary structure can inhibit flap processing at certain trinucleotide repeats in a length-dependent manner by concealing the 5' end of the flap that is necessary for both binding and cleavage by the protein encoded by this gene. Therefore, secondary structure can deter the protective function of this protein, leading to site-specific trinucleotide expansions. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Active trials

131

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.28

LOEUF

Mechanism· predicted

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?

1.28LOEUF

pLI 0.000

Z-score 0.91

OE 0.71 (0.41–1.28)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.36Z-score

OE missense 0.75 (0.66–0.85)

169 obs / 226.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.71 (0.41–1.28)

0≤0.351.4

Missense OE?0.75 (0.66–0.85)

0≤0.61.4

Synonymous OE?0.76

0≤1.21.6

LoF obs/exp: 8 / 11.3Missense obs/exp: 169 / 226.7Syn Z: 1.78

Background carrier burden — how many people carry a rare variant somewhere in FEN1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 150

374 rare PASS variants

Rare truncating (LoF)

1 in 6,800

35 rare PASS variants

Rare synonymous (reference)

1 in 360

169 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FEN1. 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 150	1 in 8,200
South Asian	~43k	1 in 190	1 in 6,200
Remaining (unassigned)	~30k	1 in 180	≈ 1 in 10,000
European (Finnish)	~27k	1 in 400	none seen
Admixed American	~22k	1 in 210	≈ 1 in 22,000
African / African American	~21k	1 in 220	1 in 3,800
East Asian	~20k	1 in 160	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 1,300	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 150	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓