SLC40A1

Chr 2AD

solute carrier family 40 member 1

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

NCBI Gene: 30061ENSG00000138449UniProt: Q9NP59OMIM: 604653

This protein functions as an iron transporter that exports Fe(2+) from cells to maintain systemic iron homeostasis, controlling dietary iron uptake and iron recycling from macrophages and hepatocytes. Mutations cause hemochromatosis type 4, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.29), indicating that complete loss of protein function is likely incompatible with normal development.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismADLOEUF 0.291 OMIM phenotype
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
2 unique Pathogenic / Likely Pathogenic· 56 VUS of 100 total submissions
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — SLC40A1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
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
1.92Z-score
OE missense 0.69 (0.62–0.78)
213 obs / 307.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.11 (0.05–0.29)
0≤0.351.4
Missense OE0.69 (0.62–0.78)
0≤0.61.4
Synonymous OE0.86
0≤1.21.6
LoF obs/exp: 3 / 26.7Missense obs/exp: 213 / 307.9Syn Z: 1.17
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveSLC40A1-related haemochromatosisLOFAR

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

DN
0.6065th %ile
GOF
0.5464th %ile
LOF
0.51top 25%

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.

Literature Evidence

DNUsing macrophages from ffe/+ mice and through expression of Fpn(ffe) in human embryonic kidney cells, Zohn et al. (2007) showed that Fpn(ffe) acted in a dominant-negative manner and prevented wildtype Fpn from localizing on the cell surface and transporting iron.PMID:17289807
GOFA novel SLC40A1 p.Y333H mutation with gain of function of ferroportin: A recurrent cause of haemochromatosis in China.PMID:30500107

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

100 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2
VUS56
Likely Benign31
Benign1
Conflicting1
2
Pathogenic
56
VUS
31
Likely Benign
1
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
2
0
2
Likely Pathogenic
0
0
0
0
0
VUS
2
53
1
0
56
Likely Benign
0
1
11
19
31
Benign
0
0
1
0
1
Conflicting
—1
Total254151991

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.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

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