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…

MultiplemechanismADLOEUF 0.523 OMIM phenotypes

Clinical Summary— HTR2A

⚡

Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.51) — some intolerance to loss-of-function variants.

📋

ClinVar Variants

28 VUS of 47 total submissions

💊

Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

📖

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

This gene — mechanism propensity

0.7036th %ile

GOF

0.78top 25%

LOF

0.3941th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

47 submitted variants in ClinVar

ClinVar

Classification Summary

VUS28

Likely Benign10

Benign4

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	27	0	0	28
Likely Benign	0	1	1	8	10
Benign	0	0	2	2	4
Total	1	28	3	10	42

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

57 pathogenic / likely-pathogenic (of 60) ClinVar copy-number / structural variants overlap HTR2A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →