SLC40A1

Chr 2AD

solute carrier family 40 member 1

Also known as: FPN, FPN1, HFE4, IREG1, MST079, MSTP079, MTP1, SLC11A3

NCBI Gene: 30061ENSG00000138449UniProt: Q9NP59

The protein encoded by this gene is a cell membrane protein that may be involved in iron export from duodenal epithelial cells. Defects in this gene are a cause of hemochromatosis type 4 (HFE4). [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Hemochromatosis, type 4MIM #606069
AD
UniProtHemochromatosis 4
358
ClinVar variants
74
Pathogenic / LP
0.99
pLI score· haploinsufficient
0
Active trials
Clinical Summary— SLC40A1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
74 Pathogenic / Likely Pathogenic· 130 VUS of 358 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.29LOEUF
pLI 0.988
Z-score 4.25
OE 0.11 (0.05–0.29)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
1.92Z-score
OE missense 0.69 (0.62–0.78)
213 obs / 307.9 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.0.11 (0.05–0.29)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.69 (0.62–0.78)
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.0.86
0≤1.21.6
LoF obs/exp: 3 / 26.7Missense obs/exp: 213 / 307.9Syn Z: 1.17

ClinVar Variant Classifications

358 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic49
Likely Pathogenic25
VUS130
Likely Benign109
Benign30
Conflicting15
49
Pathogenic
25
Likely Pathogenic
130
VUS
109
Likely Benign
30
Benign
15
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
17
32
0
49
Likely Pathogenic
0
21
4
0
25
VUS
1
108
20
1
130
Likely Benign
0
4
39
66
109
Benign
0
4
20
6
30
Conflicting
—15
Total115411573358

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

View in ClinVar →

Protein Context — Lollipop Plot

SLC40A1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SLC40A1-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 4

MIM #606069

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SLC40A1
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
Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis.
Nemeth E et al.·Int J Mol Sci
2021Review
A clinical-stage Nrf2 activator suppresses osteoclast differentiation via the iron-ornithine axis.
Dong Y et al.·Cell Metab
2024
PRMT1 driven PTX3 regulates ferritinophagy in glioma.
Lathoria K et al.·Autophagy
2023
Butyrate Prevents the Pathogenic Anemia-Inflammation Circuit by Facilitating Macrophage Iron Export.
Xiao P et al.·Adv Sci (Weinh)
2024
Erianin induces ferroptosis in GSCs via REST/LRSAM1 mediated SLC40A1 ubiquitination to overcome TMZ resistance.
Mansuer M et al.·Cell Death Dis
2024
Reactivation of MAPK-SOX2 pathway confers ferroptosis sensitivity in KRAS(G12C) inhibitor resistant tumors.
Wang K et al.·Redox Biol
2024
Exploration of molecular biomarkers in ankylosing spondylitis transcriptomics.
Ni Y et al.·Front Immunol
2024
The ferroportin disease.
Pietrangelo A·Blood Cells Mol Dis
2004Review
The Spectra of Disease-Causing Mutations in the Ferroportin 1 (SLC40A1) Encoding Gene and Related Iron Overload Phenotypes (Hemochromatosis Type 4 and Ferroportin Disease).
Uguen K et al.·Hum Mutat
2023Review
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