TPH2

Chr 12

tryptophan hydroxylase 2

Also known as: ADHD7, NTPH

NCBI Gene: 121278ENSG00000139287UniProt: Q8IWU9

This gene encodes a member of the pterin-dependent aromatic acid hydroxylase family. The encoded protein catalyzes the first and rate limiting step in the biosynthesis of serotonin, an important hormone and neurotransmitter. Mutations in this gene may be associated with psychiatric diseases such as bipolar affective disorder and major depression. [provided by RefSeq, Feb 2016]

Primary Disease Associations & Inheritance

{?Attention deficit-hyperactivity disorder, susceptibility to, 7}MIM #613003
{Unipolar depression, susceptibility to}MIM #608516
UniProtMajor depressive disorder
0
Active trials
12
Pathogenic / LP
83
ClinVar variants
5
Pubs (1 yr)
1.0
Missense Z
0.85
LOEUF
Clinical Summary— TPH2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
12 Pathogenic / Likely Pathogenic· 62 VUS of 83 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.85LOEUF
pLI 0.000
Z-score 2.16
OE 0.55 (0.37–0.85)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.00Z-score
OE missense 0.83 (0.74–0.93)
214 obs / 259.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.55 (0.37–0.85)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.83 (0.74–0.93)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.10
0≤1.21.6
LoF obs/exp: 15 / 27.1Missense obs/exp: 214 / 259.2Syn Z: -0.76
DN
0.6745th %ile
GOF
0.5465th %ile
LOF
0.3260th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

83 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
Likely Pathogenic3
VUS62
Likely Benign4
Benign5
9
Pathogenic
3
Likely Pathogenic
62
VUS
4
Likely Benign
5
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
9
0
9
Likely Pathogenic
0
0
3
0
3
VUS
0
38
19
5
62
Likely Benign
0
2
1
1
4
Benign
0
0
2
3
5
Total04034983

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

View in ClinVar →

Protein Context — Lollipop Plot

TPH2 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Predation Stress Causes Excessive Aggression in Female Mice with Partial Genetic Inactivation of Tryptophan Hydroxylase-2: Evidence for Altered Myelination-Related Processes
Svirin E et al.·Cells
2022
Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2
Zhu K et al.·Front Pharmacol
2022
Early antidepressant treatment response prediction in major depression using clinical and TPH2 DNA methylation features based on machine learning approaches
Chen B et al.·BMC Psychiatry
2023
Increase of 5-HT levels is induced both in mouse brain and HEK-293 cells following their exposure to a non-viral tryptophan hydroxylase construct
Tesoro-Cruz E et al.·Transl Psychiatry
2021Functional
Tryptophan Hydroxylase 2 Deficiency Modifies the Effects of Fluoxetine and Pargyline on the Behavior, 5-HT- and BDNF-Systems in the Brain of Zebrafish (Danio rerio)
Evsiukova VS et al.·Int J Mol Sci
2021Functional
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Extrafollicular Tph2-CD11c+CD21- B cell interactions orchestrate immune dysregulation in IgG4-related disease.
Sakamoto H et al.·Allergol Int
2026
Variants in TPH2 and ADARB1 genes in completed suicide from the Slovenian population - a follow-up to findings on attempted suicide in the Serbian population.
Karanović J et al.·World J Biol Psychiatry
2026Natural history
3,4-Methylenedioxymethamphetamine (MDMA) does not induce robust psychomotor activation and 50-kHz ultrasonic vocalisations in tryptophan hydroxylase 2 (Tph2)-deficient rats lacking serotonin in the central nervous system.
Wang T et al.·Br J Pharmacol
2026
Behavioral impact of chemogenetic manipulations of 5-HT DRN neurons in transgenic Tph2-iCre rats.
McCloskey NS et al.·Psychopharmacology (Berl)
2025Open Access
MicroRNA-669g impairs serotonin balance through TPH2 downregulation and induces behavioral deficits.
Guo S et al.·Behav Brain Res
2026
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients