TFR2

Chr 7AR

transferrin receptor 2

Also known as: HFE3, TFRC2

NCBI Gene: 7036ENSG00000106327UniProt: Q9UP52

This gene encodes a single-pass type II membrane protein, which is a member of the transferrin receptor-like family. This protein mediates cellular uptake of transferrin-bound iron, and may be involved in iron metabolism, hepatocyte function and erythrocyte differentiation. Mutations in this gene have been associated with hereditary hemochromatosis type III. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, May 2011]

Primary Disease Associations & Inheritance

Hemochromatosis, type 3MIM #604250
AR
UniProtHemochromatosis 3
577
ClinVar variants
94
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TFR2
🧬
Gene-Disease Validity (ClinGen)
hemochromatosis type 3 · 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
94 Pathogenic / Likely Pathogenic· 172 VUS of 577 total submissions

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.
0.77LOEUF
pLI 0.000
Z-score 2.72
OE 0.53 (0.38–0.77)
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.
1.14Z-score
OE missense 0.85 (0.78–0.93)
401 obs / 470.9 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.0.53 (0.38–0.77)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.85 (0.78–0.93)
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.0.89
0≤1.21.6
LoF obs/exp: 21 / 39.4Missense obs/exp: 401 / 470.9Syn Z: 1.18

ClinVar Variant Classifications

577 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic44
Likely Pathogenic50
VUS172
Likely Benign255
Benign14
Conflicting42
44
Pathogenic
50
Likely Pathogenic
172
VUS
255
Likely Benign
14
Benign
42
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
16
3
25
0
44
Likely Pathogenic
28
3
19
0
50
VUS
1
137
24
10
172
Likely Benign
1
14
113
127
255
Benign
0
0
9
5
14
Conflicting
—42
Total46157190142577

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

View in ClinVar →

Protein Context — Lollipop Plot

TFR2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

TFR2-related haemochromatosis

definitive
ARLoss Of FunctionAbsent Gene Product
Skin
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Hemochromatosis, type 3

MIM #604250

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — TFR2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Haemochromatosis.
Brissot P et al.·Nat Rev Dis Primers
2018Review
Transferrin and transferrin receptors update.
Kawabata H·Free Radic Biol Med
2019Review
Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment.
Pietrangelo A·Gastroenterology
2010Review
Juvenile haemochromatosis.
Griffiths WJH et al.·Lancet Child Adolesc Health
2021Review
Non-HFE hemochromatosis.
Pietrangelo A·Semin Liver Dis
2005Review
Hepcidin in hepatocellular carcinoma.
Joachim JH et al.·Br J Cancer
2022Review
Current Landscape of Hepcidin Therapeutics.
Nai A et al.·Adv Exp Med Biol
2025Review
Genetics of haemochromatosis.
Bomford A·Lancet
2002Review
Inherited disorders of iron metabolism.
Camaschella C et al.·Curr Opin Pediatr
2011Review
Transferrin receptor 2 mitigates periodontitis-driven alveolar bone loss.
Lösser L et al.·J Cell Physiol
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools