TMPRSS6

Chr 22AR

transmembrane serine protease 6

Also known as: IRIDA, MT2

NCBI Gene: 164656ENSG00000187045UniProt: Q8IU80

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]

Primary Disease Associations & Inheritance

Iron-refractory iron deficiency anemiaMIM #206200
AR
434
ClinVar variants
55
Pathogenic / LP
0.00
pLI score
4
Active trials
Clinical Summary— TMPRSS6
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
55 Pathogenic / Likely Pathogenic· 221 VUS of 434 total submissions
💊
Clinical Trials
4 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.
0.72LOEUF
pLI 0.000
Z-score 3.06
OE 0.51 (0.36–0.72)
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.
0.21Z-score
OE missense 0.97 (0.90–1.05)
485 obs / 498.4 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.0.51 (0.36–0.72)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.90–1.05)
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.1.08
0≤1.21.6
LoF obs/exp: 23 / 45.2Missense obs/exp: 485 / 498.4Syn Z: -0.90

ClinVar Variant Classifications

434 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic40
Likely Pathogenic15
VUS221
Likely Benign72
Benign51
Conflicting23
40
Pathogenic
15
Likely Pathogenic
221
VUS
72
Likely Benign
51
Benign
23
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
2
26
0
40
Likely Pathogenic
6
3
6
0
15
VUS
3
192
20
6
221
Likely Benign
5
10
25
32
72
Benign
2
4
30
15
51
Conflicting
—23
Total2821110753422

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.

Gene2Phenotype Curations

TMPRSS6-related iron-refractory iron deficiency anemia

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

Iron-refractory iron deficiency anemia

MIM #206200

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Iron metabolism and iron disorders revisited in the hepcidin era.
Camaschella C et al.·Haematologica
2020Review
How I treat iron-refractory iron deficiency anaemia-An expert opinion-based treatment guidance for children and adults.
Hoving V et al.·Br J Haematol
2025Review
Iron-refractory iron deficiency anemia (IRIDA).
Heeney MM et al.·Hematol Oncol Clin North Am
2014Review
Targeting the Liver Serine Protease TMPRSS6 Ameliorates Steatosis and Attenuates Fibrosis in Experimental MASLD.
Pettinato M et al.·Liver Int
2025
Ziltivekimab for Treatment of Anemia of Inflammation in Patients on Hemodialysis: Results from a Phase 1/2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.
Pergola PE et al.·J Am Soc Nephrol
2021Cohort
Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis.
Ramsay AJ et al.·Haematologica
2009Review
Association of common TMPRSS6 and TF gene variants with hepcidin and iron status in healthy rural Gambians.
Jallow MW et al.·Sci Rep
2021
Inherited disorders of iron metabolism.
Camaschella C et al.·Curr Opin Pediatr
2011Review
Hepcidin, an overview of biochemical and clinical properties.
Rauf A et al.·Steroids
2020Review
Combination of a TGF-β ligand trap (RAP-GRL) and TMPRSS6-ASO is superior for correcting β-thalassemia.
Guerra A et al.·Am J Hematol
2024
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
Polycythemia Vera

Study to Assess SLN124 in Patients With Polycythemia Vera

ACTIVE NOT RECRUITING
NCT05499013Phase PHASE1, PHASE2Silence Therapeutics plcStarted 2023-01-26
SLN124Placebo
Phlebotomy Dependent Polycythemia Vera

A Study to Evaluate Sapablursen (Formerly ISIS 702843, IONIS-TMPRSS6-LRx) in Patients With Polycythemia Vera

ACTIVE NOT RECRUITING
NCT05143957Phase PHASE2Ionis Pharmaceuticals, Inc.Started 2021-12-30
sapablursen
Adherence to a Personalised Nutrition Programme

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

NOT YET RECRUITING
NCT07407556Phase NAAlexandra KingStarted 2026-03
Psychology-tailored messageNeutral message
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

RECRUITING
NCT06421636Phase PHASE2Regeneron PharmaceuticalsStarted 2024-09-30
REGN7999Placebo

External Resources

Links to major genomics databases and tools