HTR1D

Chr 1

5-hydroxytryptamine receptor 1D

Also known as: 5-HT1D, HT1DA, HTR1DA, HTRL, RDC4

HTR1D encodes a G-protein coupled receptor for serotonin that inhibits adenylate cyclase activity and regulates neurotransmitter release in the brain. Mutations cause autosomal dominant episodic cranial sensory neuropathy with onset typically in childhood or adolescence. The gene shows low constraint to loss-of-function variation, suggesting that complete loss of function may be tolerated.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 1.30
Clinical SummaryHTR1D
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
1.30LOEUF
pLI 0.001
Z-score 0.96
OE 0.66 (0.361.30)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
0.09Z-score
OE missense 0.98 (0.881.10)
221 obs / 224.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.66 (0.361.30)
00.351.4
Missense OE0.98 (0.881.10)
00.61.4
Synonymous OE0.97
01.21.6
LoF obs/exp: 6 / 9.1Missense obs/exp: 221 / 224.8Syn Z: 0.27
DN
0.77top 25%
GOF
0.80top 10%
LOF
0.2581th %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

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

HTR1D · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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