PTS

Chr 11AR

6-pyruvoyltetrahydropterin synthase

Also known as: PTPS

NCBI Gene: 5805ENSG00000150787UniProt: Q03393

The enzyme encoded by this gene catalyzes the elimination of inorganic triphosphate from dihydroneopterin triphosphate, which is the second and irreversible step in the biosynthesis of tetrahydrobiopterin from GTP. Tetrahydrobiopterin, also known as BH(4), is an essential cofactor and regulator of various enzyme activities, including enzymes involved in serotonin biosynthesis and NO synthase activity. Mutations in this gene result in hyperphenylalaninemia. [provided by RefSeq, Oct 2008]

Primary Disease Associations & Inheritance

Hyperphenylalaninemia, BH4-deficient, AMIM #261640
AR
374
ClinVar variants
117
Pathogenic / LP
0.00
pLI score
12
Active trials
Clinical Summary— PTS
🧬
Gene-Disease Validity (ClinGen)
BH4-deficient hyperphenylalaninemia A · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
117 Pathogenic / Likely Pathogenic· 74 VUS of 374 total submissions
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available

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.
1.69LOEUF
pLI 0.000
Z-score 0.07
OE 0.97 (0.57–1.69)
Tolerant

Highly tolerant — LoF variants common in population

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.
0.13Z-score
OE missense 0.96 (0.80–1.16)
76 obs / 79.1 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.0.97 (0.57–1.69)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.96 (0.80–1.16)
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.1.22
0≤1.21.6
LoF obs/exp: 8 / 8.2Missense obs/exp: 76 / 79.1Syn Z: -0.93

ClinVar Variant Classifications

374 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic60
Likely Pathogenic57
VUS74
Likely Benign150
Benign15
Conflicting18
60
Pathogenic
57
Likely Pathogenic
74
VUS
150
Likely Benign
15
Benign
18
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
20
29
0
60
Likely Pathogenic
21
26
9
1
57
VUS
1
56
15
2
74
Likely Benign
0
1
93
56
150
Benign
0
0
14
1
15
Conflicting
—18
Total3310316060374

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

View in ClinVar →

Protein Context — Lollipop Plot

PTS · protein map & ClinVar variants

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

Gene2Phenotype Curations

PTS-related 6-pyruvoyltetrahydropterin synthase deficiency

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Hyperphenylalaninemia, BH4-deficient, A

MIM #261640

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — PTS
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Single-cell RNA sequencing of OSCC primary tumors and lymph nodes reveals distinct origin and phenotype of fibroblasts.
Zhang Q et al.·Cancer Lett
2024
The post-thrombotic syndrome.
Kahn SR·Hematology Am Soc Hematol Educ Program
2010Review
The postthrombotic syndrome.
Pesavento R et al.·Intern Emerg Med
2010Review
Postthrombotic syndrome.
Pesavento R et al.·Semin Thromb Hemost
2006Review
Relationship of Genotype, Phenotype, and Treatment in Dopa-Responsive Dystonia: MDSGene Review.
Weissbach A et al.·Mov Disord
2022Review
Epidemiology of the post-thrombotic syndrome.
Galanaud JP et al.·Thromb Res
2018Review
The post-thrombotic syndrome.
Bernardi E et al.·Curr Opin Pulm Med
2000Review
Scoring Systems for Postthrombotic Syndrome.
Wik HS et al.·Semin Thromb Hemost
2017Review
Diagnostic scales for the post-thrombotic syndrome.
Wik HS et al.·Thromb Res
2018Review
[Postthrombotic syndome-a complex clinical picture].
Kahle B·Dermatologie (Heidelb)
2023Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Intracranial MeningiomaRecurrent MeningiomaNF2 Gene Mutation

Vismodegib, FAK Inhibitor GSK2256098, Capivasertib, and Abemaciclib in Treating Patients With Progressive Meningiomas

RECRUITING
NCT02523014Phase PHASE2Alliance for Clinical Trials in OncologyStarted 2015-09-28
VismodegibFAK Inhibitor GSK2256098Capivasertib
Stage IB Lung Non-Small Cell Carcinoma AJCC v7Stage II Lung Non-Small Cell Cancer AJCC v7Stage IIIA Lung Non-Small Cell Cancer AJCC v7

Nivolumab After Surgery and Chemotherapy in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer (An ALCHEMIST Treatment Trial)

ACTIVE NOT RECRUITING
NCT02595944Phase PHASE3National Cancer Institute (NCI)Started 2016-07-22
Biospecimen CollectionComputed TomographyEchocardiography Test
Lung Cancer

Efficacy and Safety of Intratumoral Toluenesulfonamide (PTS) Injection in Stage IV Driver Gene-Negative NSCLC With/Without Chemoimmunotherapy

RECRUITING
NCT06607796Phase PHASE3Zhou ChengzhiStarted 2024-03-01
Toluenesulfonamide (PTS) Intratumoral Injection
Advanced Malignant Solid NeoplasmMetastatic Malignant Solid NeoplasmNF1 Mutation Positive Malignant Peripheral Nerve Sheath Tumor

Testing Whether Cancers With Specific Mutations Respond Better to Glutaminase Inhibitor, Telaglenastat Hydrochloride, Anti-Cancer Treatment, BeGIN Study

ACTIVE NOT RECRUITING
NCT03872427Phase PHASE2National Cancer Institute (NCI)Started 2019-12-14
Biospecimen CollectionComputed TomographyMagnetic Resonance Imaging
Advanced LymphomaAdvanced Malignant Solid NeoplasmBladder Carcinoma

Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)

ACTIVE NOT RECRUITING
NCT02465060Phase PHASE2National Cancer Institute (NCI)Started 2015-08-17
AdavosertibAfatinibAfatinib Dimaleate
Breast CancerPALB2-Mutated Breast CarcinomaHER2-negative Breast Cancer

Phase Ib Study of Axatilimab in Combination With Olaparib in BRCA1/2 and PALB2- Associated Metastatic HER2-negative Breast Cancer

RECRUITING
NCT06488378Phase PHASE1Dana-Farber Cancer InstituteStarted 2024-08-13
AxatilimabOlaparib
Acinar Cell CarcinomaAdenoid Cystic CarcinomaAdrenal Cortical Carcinoma

Nivolumab and Ipilimumab in Treating Patients With Rare Tumors

ACTIVE NOT RECRUITING
NCT02834013Phase PHASE2National Cancer Institute (NCI)Started 2017-01-30
Biospecimen CollectionComputed TomographyEchocardiography Test
Muscle Invasive Bladder Cancer

Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Phase 1b Study in Pts w/ Muscle Invasive Bladder Cancer

ACTIVE NOT RECRUITING
NCT02546661Phase PHASE1AstraZenecaStarted 2016-12-28
AZD4547MEDI4736Olaparib
Stage IB Lung Non-Small Cell Carcinoma AJCC v7Stage II Lung Non-Small Cell Cancer AJCC v7Stage IIA Lung Cancer AJCC v8

Genetic Testing in Screening Patients With Stage IB-IIIA Non-small Cell Lung Cancer That Has Been or Will Be Removed by Surgery (The ALCHEMIST Screening Trial)

ACTIVE NOT RECRUITING
NCT02194738Phase NANational Cancer Institute (NCI)Started 2014-09-26
Biospecimen CollectionCarboplatinCisplatin
Locally Advanced Unresectable Primary Central ChondrosarcomaMetastatic Primary Central ChondrosarcomaUnresectable Primary Central Chondrosarcoma

Testing the Combination of Belinostat and SGI-110 (Guadecitabine) or ASTX727 for the Treatment of Unresectable and Metastatic Conventional Chondrosarcoma

ACTIVE NOT RECRUITING
NCT04340843Phase PHASE2National Cancer Institute (NCI)Started 2020-09-08
BelinostatBiopsy ProcedureBiospecimen Collection
Clinical Stage III Cutaneous Melanoma AJCC v8Clinical Stage IV Cutaneous Melanoma AJCC v8Metastatic Cutaneous Melanoma

Physician/Patient Choice of Either High-Dose Recombinant Interferon Alfa-2B or Ipilimumab, Versus Pembrolizumab in Treating Patients With Stage III-IV High Risk Melanoma That Has Been Removed by Surgery

ACTIVE NOT RECRUITING
NCT02506153Phase PHASE3National Cancer Institute (NCI)Started 2015-11-10
Biospecimen CollectionComputed TomographyIpilimumab
Hodgkin LymphomaNon-Hodgkin Lymphoma

Evaluating the Impact of Social and Genetic Factors on Outcomes in Adolescent and Young Adult Cancer Survivors

RECRUITING
NCT06002828ECOG-ACRIN Cancer Research GroupStarted 2023-10-13
Biospecimen CollectionQuality-of-Life AssessmentQuestionnaire Administration

External Resources

Links to major genomics databases and tools