TMPRSS6

Chr 22

transmembrane serine protease 6

Also known as: IRIDA, MT2

NCBI Gene: 164656 ENSG00000187045 UniProt: Q8IU80

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.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a type II transmembrane serine proteinase that is found attached to the cell surface. The encoded protein may be involved in matrix remodeling processes in the liver. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtIron-refractory iron deficiency anemia

Clinical highlights

Gene-disease validity (ClinGen)

IRIDA syndrome · ARDefinitivesufficient evidence for diagnostic panels

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.72

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — TMPRSS6

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.72LOEUF

pLI 0.000

Z-score 3.06

OE 0.51 (0.36–0.72)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.21Z-score

OE missense 0.97 (0.90–1.05)

485 obs / 498.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.51 (0.36–0.72)

0≤0.351.4

Missense OE?0.97 (0.90–1.05)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 23 / 45.2Missense obs/exp: 485 / 498.4Syn Z: -0.90

ClinVar Variant Classifications

0 submitted variants in ClinVar

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.

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

📖

GeneReview available — TMPRSS6

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Non-Transfusion Dependent Beta-Thalassemia (NTDT)

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

ACTIVE NOT RECRUITING

NCT06421636Phase PHASE2Regeneron PharmaceuticalsStarted 2024-09-30

REGN7999Placebo

Polycythemia Vera

Study to Assess SLN124 in Patients With Polycythemia Vera

ACTIVE NOT RECRUITING

NCT05499013Phase PHASE1, PHASE2Silence Therapeutics plcStarted 2023-01-26

SLN124Placebo

Adherence to a Personalised Nutrition Programme

Exploring the Use of Genetic and Behavioural Data in Tailoring Dietary and Lifestyle Support

ACTIVE NOT RECRUITING

NCT07407556Phase NAAlexandra KingStarted 2026-02-13