TMPRSS6
Chr 22ARtransmembrane serine protease 6
Also known as: IRIDA, MT2
TMPRSS6 encodes a membrane-bound serine protease that cleaves hemojuvelin to regulate hepcidin expression and maintain iron homeostasis. Autosomal recessive mutations cause iron-refractory iron deficiency anemia, a condition characterized by severe iron deficiency that does not respond to oral iron supplementation. The gene is not highly constrained against loss-of-function variants.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.
The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
436 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 18 | 3 | 19 | 0 | 40 |
Likely Pathogenic | 11 | 3 | 1 | 0 | 15 |
VUS | 3 | 195 | 19 | 6 | 223 |
Likely Benign | 5 | 10 | 25 | 32 | 72 |
Benign | 2 | 4 | 30 | 15 | 51 |
Conflicting | — | 23 | |||
| Total | 39 | 215 | 94 | 53 | 424 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
TMPRSS6 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
A Study to Test the Safety, Tolerability, and Efficacy of an Antibody, REGN7999, Injected Under the Skin for the Treatment of Iron Overload in Adult Participants With Non-Transfusion Dependent β-thalassemia, Using MRI Scans to Measure Iron Levels in the Body
RECRUITINGA Study to Evaluate Sapablursen (Formerly ISIS 702843, IONIS-TMPRSS6-LRx) in Patients With Polycythemia Vera
ACTIVE NOT RECRUITINGStudy to Assess SLN124 in Patients With Polycythemia Vera
ACTIVE NOT RECRUITINGExploring the Use of Genetic and Behavioural Data in Tailoring Dietary and Lifestyle Support
ACTIVE NOT RECRUITINGExternal Resources
Links to major genomics databases and tools