CHAT

Chr 10AR

choline O-acetyltransferase

Also known as: CHOACTASE, CMS1A, CMS1A2, CMS6

NCBI Gene: 1103 ENSG00000070748 UniProt: P28329 OMIM: 118490

This gene encodes choline acetyltransferase, the enzyme that catalyzes acetylcholine biosynthesis in cholinergic neurons. Mutations cause congenital myasthenic syndrome type 6 with episodic apnea through autosomal recessive inheritance. The pathogenic mechanism involves presynaptic dysfunction due to impaired acetylcholine synthesis at the neuromuscular junction.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, Mechanism

This gene encodes an enzyme which catalyzes the biosynthesis of the neurotransmitter acetylcholine. This gene product is a characteristic feature of cholinergic neurons, and changes in these neurons may explain some of the symptoms of Alzheimer's disease. Polymorphisms in this gene have been associated with Alzheimer's disease and mild cognitive impairment. Mutations in this gene are associated with congenital myasthenic syndrome associated with episodic apnea. Multiple transcript variants encoding different isoforms have been found for this gene, and some of these variants have been shown to encode more than one isoform. [provided by RefSeq, May 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Myasthenic syndrome, congenital, 6, presynapticMIM #254210

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · congenital myasthenic syndrome 6 · AR · ClinGen 2025

Active trials

1617

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.88

LOEUF

Mechanism· predicted

📖

GeneReview available — CHAT

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.88LOEUF

pLI 0.000

Z-score 2.11

OE 0.62 (0.44–0.88)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.30Z-score

OE missense 0.96 (0.89–1.04)

414 obs / 431.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.62 (0.44–0.88)

0≤0.351.4

Missense OE?0.96 (0.89–1.04)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 22 / 35.6Missense obs/exp: 414 / 431.3Syn Z: -1.44

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 52

1,015 rare PASS variants

Rare truncating (LoF)

1 in 930

147 rare PASS variants

Rare synonymous (reference)

1 in 93

433 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CHAT. 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 74	1 in 1,500
South Asian	~43k	1 in 46	1 in 530
Remaining (unassigned)	~30k	1 in 37	1 in 530
European (Finnish)	~27k	1 in 110	1 in 2,000
Admixed American	~22k	1 in 39	1 in 770
African / African American	~21k	1 in 39	1 in 1,600
East Asian	~20k	1 in 67	1 in 890
Ashkenazi Jewish	~13k	1 in 120	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 52	≈ 1 in 960

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): 15 of 15 coding exons well covered in gnomAD exomes. Genomes: 14 of 15 (exon 5 below).? see exons ↓