TDO2

Chr 4AR

tryptophan 2,3-dioxygenase

Also known as: HYPTRP, TDO, TO, TPH2, TRPO

NCBI Gene: 6999ENSG00000151790UniProt: P48775

The protein is a heme-dependent dioxygenase that catalyzes the first and rate-limiting step of tryptophan metabolism, converting L-tryptophan to N-formyl-kynurenine in the kynurenine pathway. Mutations cause hypertryptophanemia with autosomal recessive inheritance. The gene is highly intolerant to loss-of-function variants, indicating it is essential for normal cellular function.

Summary from RefSeq, OMIM, UniProt
Research Assistant →

Primary Disease Associations & Inheritance

[?Hypertryptophanemia]MIM #600627
AR
0
Active trials
47
Pubs (1 yr)
29
P/LP submissions
0%
P/LP missense
1.04
LOEUF
DN
Mechanism· predicted
Clinical Summary— TDO2
🧬
Gene-Disease Validity (ClinGen)
familial hypertryptophanemia · ARLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
29 unique Pathogenic / Likely Pathogenic· 55 VUS of 98 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
1.04LOEUF
pLI 0.000
Z-score 1.40
OE 0.71 (0.49–1.04)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-0.22Z-score
OE missense 1.04 (0.93–1.17)
210 obs / 201.2 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.71 (0.49–1.04)
0≤0.351.4
Missense OE1.04 (0.93–1.17)
0≤0.61.4
Synonymous OE1.04
0≤1.21.6
LoF obs/exp: 19 / 26.8Missense obs/exp: 210 / 201.2Syn Z: -0.30
DN
0.6842th %ile
GOF
0.5857th %ile
LOF
0.2679th %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

98 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic26
Likely Pathogenic3
VUS55
Likely Benign4
Benign3
26
Pathogenic
3
Likely Pathogenic
55
VUS
4
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
26
0
26
Likely Pathogenic
0
0
3
0
3
VUS
0
47
8
0
55
Likely Benign
0
1
1
2
4
Benign
0
2
0
1
3
Total05038391

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

View in ClinVar →

Protein Context — Lollipop Plot

TDO2 · 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
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
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
TDO2-Associated Tryptophan Metabolism Correlates with Impaired Tertiary Lymphoid Structure Maturation and Reduced B Cell Class Switching in Breast Cancer.
Yang W et al.·Oncol Res
2026Open Access
IL4I1⁺ Macrophages and TDO2⁺ Myofibroblasts Drive AhR-Mediated Immunosuppression and Ferroptosis Resistance in Solid Predominant Lung Adenocarcinoma.
Wang Z et al.·Adv Sci (Weinh)
2026Open Access
SIRPA, BTN3A1, and TDO2 in osteosarcoma: a prognostic triad with therapeutic implications from integrated genomic and pharmacogenomic data.
Zhang HJ et al.·J Orthop Surg Res
2025Open Access
AR to GR switch modulates differential TDO2-Kyn-AhR signalling to promote the survival and recurrence of treatment-induced dormant cells in prostate cancer.
Li S et al.·Cell Discov
2025Open Access
Kynureninase expression is associated with immunologically hot tumors and better prognosis in IDO1/TDO2-expressing breast carcinomas.
Giatromanolaki A et al.·Pathol Res Pract
2025
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