SLC40A1

Chr 2

solute carrier family 40 member 1

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.

ResearchSummary from RefSeq, OMIM, UniProt

Transports Fe(2+) from the inside of a cell to the outside of the cell, playing a key role for maintaining systemic iron homeostasis (PubMed:15692071, PubMed:22178646, PubMed:22682227, PubMed:24304836, PubMed:29237594, PubMed:29599243, PubMed:30247984). Transports iron from intestinal, splenic, hepatic cells, macrophages and erythrocytes into the blood to provide iron to other tissues (By similarity). Controls therefore dietary iron uptake, iron recycling by macrophages and erythrocytes, and release of iron stores in hepatocytes (By similarity). When iron is in excess in serum, circulating HAMP/hepcidin levels increase resulting in a degradation of SLC40A1, thus limiting the iron efflux to plasma (PubMed:22682227, PubMed:29237594, PubMed:32814342)

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.29

Clinical Summary— SLC40A1

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Gene-Disease Validity (ClinGen)

hemochromatosis type 4 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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Some data sources returned errors (2)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

omim: Error: OMIM fetch failed: 429

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 OE?0.11 (0.05–0.29)

0≤0.351.4

Missense OE?0.69 (0.62–0.78)

0≤0.61.4

Synonymous OE?0.86

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

This gene — mechanism propensity

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

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.1

GOFA novel SLC40A1 p.Y333H mutation with gain of function of ferroportin: A recurrent cause of haemochromatosis in China.2

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

References