NAT2

Chr 8AR

N-acetyltransferase 2

Also known as: AAC2, NAT-2, PNAT

NCBI Gene: 10 ENSG00000156006 UniProt: P11245 OMIM: 612182

The encoded enzyme catalyzes N- or O-acetylation of arylamine and hydrazine substrates, participating in drug detoxification and carcinogen bioactivation. Mutations cause slow acetylation phenotype, which affects drug metabolism rates and is associated with increased cancer risk and drug toxicity. This follows autosomal recessive inheritance and shows low constraint against loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an enzyme that functions to both activate and deactivate arylamine and hydrazine drugs and carcinogens. Polymorphisms in this gene are responsible for the N-acetylation polymorphism in which human populations segregate into rapid, intermediate, and slow acetylator phenotypes. Polymorphisms in this gene are also associated with higher incidences of cancer and drug toxicity. A second polymorphic arylamine N-acetyltransferase gene (NAT1), is located near this gene (NAT2). [provided by RefSeq, Sep 2019]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

[Acetylation, slow]MIM #243400

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.79

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.79LOEUF

pLI 0.000

Z-score -0.22

OE 1.09 (0.63–1.79)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.38Z-score

OE missense 1.32 (1.17–1.49)

196 obs / 148.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.09 (0.63–1.79)

0≤0.351.4

Missense OE?1.32 (1.17–1.49)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 8 / 7.4Missense obs/exp: 196 / 148.6Syn Z: -0.14

Background carrier burden — how many people carry a rare variant somewhere in NAT2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 100

465 rare PASS variants

Rare truncating (LoF)

1 in 1,700

57 rare PASS variants

Rare synonymous (reference)

1 in 410

150 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NAT2. 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 190	1 in 1,900
South Asian	~43k	1 in 75	1 in 1,800
Remaining (unassigned)	~30k	1 in 81	1 in 2,000
European (Finnish)	~27k	1 in 240	≈ 1 in 26,000
Admixed American	~22k	1 in 85	≈ 1 in 7,400
African / African American	~21k	1 in 130	1 in 990
East Asian	~20k	1 in 150	1 in 2,500
Ashkenazi Jewish	~13k	1 in 350	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 170	≈ 1 in 720

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 ↓