HTR2A

Chr 13AD

5-hydroxytryptamine receptor 2A

Also known as: 5-HT2A, HTR2

NCBI Gene: 3356 ENSG00000102468 UniProt: P28223 OMIM: 182135

This gene encodes a G-protein coupled receptor for serotonin that activates phospholipase C-beta signaling and affects neural activity, perception, cognition and mood. Mutations are associated with susceptibility to schizophrenia and obsessive-compulsive disorder, as well as altered response to antidepressant therapy in major depressive disorder. The inheritance pattern is autosomal dominant.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes one of the receptors for serotonin, a neurotransmitter with many roles. Mutations in this gene are associated with susceptibility to schizophrenia and obsessive-compulsive disorder, and are also associated with response to the antidepressant citalopram in patients with major depressive disorder (MDD). MDD patients who also have a mutation in intron 2 of this gene show a significantly reduced response to citalopram as this antidepressant downregulates expression of this gene. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

{Major depressive disorder, response to citalopram therapy in}MIM #608516

{Obsessive-compulsive disorder, susceptibility to}MIM #164230

{Schizophrenia, susceptibility to}MIM #181500

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

130

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.52

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — HTR2A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.52LOEUF

pLI 0.511

Z-score 2.86

OE 0.20 (0.09–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.75Z-score

OE missense 0.69 (0.61–0.78)

177 obs / 255.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.20 (0.09–0.52)

0≤0.351.4

Missense OE?0.69 (0.61–0.78)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 3 / 14.9Missense obs/exp: 177 / 255.7Syn Z: -0.15

Background carrier burden — how many people carry a rare variant somewhere in HTR2A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 260

473 rare PASS variants

Rare truncating (LoF)

1 in 6,400

51 rare PASS variants

Rare synonymous (reference)

1 in 230

219 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HTR2A. 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 310	1 in 6,300
South Asian	~43k	1 in 190	≈ 1 in 11,000
Remaining (unassigned)	~30k	1 in 170	≈ 1 in 30,000
European (Finnish)	~27k	1 in 220	1 in 5,300
Admixed American	~22k	1 in 260	1 in 3,700
African / African American	~21k	1 in 140	≈ 1 in 8,400
East Asian	~20k	1 in 190	none seen
Ashkenazi Jewish	~13k	1 in 340	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 290	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 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓