HTR2C

Chr X

5-hydroxytryptamine receptor 2C

Also known as: 5-HT1C, 5-HT2C, 5-HTR2C, 5HTR2C, HTR1C

NCBI Gene: 3358 ENSG00000147246 UniProt: P28335 OMIM: 312861

The HTR2C protein is a G-protein-coupled receptor that responds to serotonin signaling and activates phospholipase C-beta through G(q)/G(11) proteins, modulating neuronal activity, appetite regulation, and stress responses. Mutations in HTR2C cause X-linked intellectual disability with associated features that may include obesity, behavioral problems, and seizures. This gene follows X-linked inheritance and has low constraint against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a seven-transmembrane G-protein-coupled receptor. The encoded protein responds to signaling through the neurotransmitter serotonin. The mRNA of this gene is subject to multiple RNA editing events, where adenosine residues encoded by the genome are converted to inosines. RNA editing is predicted to alter the structure of the second intracellular loop, thereby generating alternate protein forms with decreased ability to interact with G proteins. Abnormalities in RNA editing of this gene have been detected in victims of suicide that suffer from depression. In addition, naturally-occuring variation in the promoter and 5' non-coding and coding regions of this gene may show statistically-significant association with mental illness and behavioral disorders. Alternative splicing results in multiple different transcript variants. [provided by RefSeq, Jan 2015]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.87

Clinical Summary— HTR2C

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Population Constraint (gnomAD)

Low constraint (pLI 0.04) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 72 VUS of 144 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.87LOEUF

pLI 0.037

Z-score 1.87

OE 0.38 (0.19–0.87)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.21Z-score

OE missense 0.76 (0.66–0.87)

147 obs / 194.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.38 (0.19–0.87)

0≤0.351.4

Missense OE?0.76 (0.66–0.87)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 4 / 10.6Missense obs/exp: 147 / 194.3Syn Z: 0.96

This gene — mechanism propensity

0.76top 25%

GOF

0.83top 10%

LOF

0.2873th %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

144 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS72

Likely Benign37

Benign4

Likely Pathogenic

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	1	0	0	0	1
VUS	3	68	0	1	72
Likely Benign	0	8	5	24	37
Benign	0	1	3	0	4
Total	4	77	8	25	114

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

View in ClinVar →

71 pathogenic / likely-pathogenic (of 77) ClinVar copy-number / structural variants overlap HTR2C — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →