TMPRSS6

Chr 22AR

transmembrane serine protease 6

Also known as: IRIDA, MT2

NCBI Gene: 164656ENSG00000187045UniProt: Q8IU80OMIM: 609862

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]

GeneReviewsOMIMResearchGenerating clinical summary…
LOFmechanismARLOEUF 0.721 OMIM phenotype
Clinical Summary— TMPRSS6
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Gene-Disease Validity (ClinGen)
IRIDA syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
36 unique Pathogenic / Likely Pathogenic· 221 VUS of 413 total submissions
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Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — TMPRSS6
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

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
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveTMPRSS6-related iron-refractory iron deficiency anemiaLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.6647th %ile
GOF
0.7029th %ile
LOF
0.3065th %ile

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

413 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic14
VUS221
Likely Benign71
Benign51
Conflicting22
22
Pathogenic
14
Likely Pathogenic
221
VUS
71
Likely Benign
51
Benign
22
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
18
3
1
0
22
Likely Pathogenic
11
3
0
0
14
VUS
3
196
16
6
221
Likely Benign
5
9
25
32
71
Benign
2
4
30
15
51
Conflicting
—22
Total392157253401

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap TMPRSS6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

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