SLC39A14

Chr 8ADAR

solute carrier family 39 member 14

Also known as: HCIN, HMNDYT2, LZT-Hs4, NET34, ZIP14, cig19

NCBI Gene: 23516ENSG00000104635UniProt: Q15043

This gene encodes a member of the the SLC39A family of divalent metal transporters that mediates the cellular uptake of manganese, zinc, iron, and cadmium. The encoded protein contains eight transmembrane domains, a histidine-rich motif, and a metalloprotease motif, and is expressed on the plasma membrane and the endocytic vesicle membrane. It is an important transporter of nontransferrin-bound iron and a critical regulator of manganese homeostasis. Naturally occurring mutations in this gene are associated with neurodegeneration with brain iron accumulation and early-onset parkinsonism-dystonia with hypermanganesemia. [provided by RefSeq, May 2017]

Primary Disease Associations & Inheritance

?Hyperostosis cranalis internaMIM #144755
AD
Hypermanganesemia with dystonia 2MIM #617013
AR
UniProtHyperostosis cranialis interna
367
ClinVar variants
95
Pathogenic / LP
0.15
pLI score
0
Active trials
Clinical Summary— SLC39A14
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.
📋
ClinVar Variants
95 Pathogenic / Likely Pathogenic· 106 VUS of 367 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.55LOEUF
pLI 0.150
Z-score 2.97
OE 0.26 (0.14–0.55)
Moderately constrained

More LoF-intolerant than ~75% 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 0.68 (0.60–0.77)
194 obs / 285.1 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.0.26 (0.14–0.55)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.68 (0.60–0.77)
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.0.93
0≤1.21.6
LoF obs/exp: 5 / 19.0Missense obs/exp: 194 / 285.1Syn Z: 0.62

ClinVar Variant Classifications

367 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic87
Likely Pathogenic8
VUS106
Likely Benign120
Benign40
Conflicting6
87
Pathogenic
8
Likely Pathogenic
106
VUS
120
Likely Benign
40
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
5
80
0
87
Likely Pathogenic
1
1
6
0
8
VUS
5
81
18
2
106
Likely Benign
0
9
38
73
120
Benign
0
2
29
9
40
Conflicting
—6
Total89817184367

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

View in ClinVar →

Protein Context — Lollipop Plot

SLC39A14 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SLC39A14-related early onset dystonia parkinsonism

definitive
ARLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure
Dev. Disorders
G2P ↗
frameshift variantstop gainedmissense variantwhole partial gene deletion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Hyperostosis cranalis interna

MIM #144755

Molecular basis of disorder known

Autosomal dominant

Hypermanganesemia with dystonia 2

MIM #617013

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — SLC39A14
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genotype-Phenotype Relations for the Dystonia-Parkinsonism Genes GLB1, SLC6A3, SLC30A10, SLC39A14, and PLA2G6: MDSGene Systematic Review.
Rodriguez-Antiguedad J et al.·Int J Mol Sci
2025Review
Intratumoral Brevibacillus parabrevis enhances antitumor immunity by inhibiting NK cell ferroptosis in hepatocellular carcinoma.
Pan B et al.·Cell Death Dis
2025
Genetic Disorders of Manganese Metabolism.
Anagianni S et al.·Curr Neurol Neurosci Rep
2019Review
Mesenchymal stem cell-derived extracellular vesicles attenuate ferroptosis in aged hepatic ischemia/reperfusion injury by transferring miR-1275.
Gong Y et al.·Redox Biol
2025
Hereditary Disorders of Manganese Metabolism: Pathophysiology of Childhood-Onset Dystonia-Parkinsonism in SLC39A14 Mutation Carriers and Genetic Animal Models.
Rodichkin AN et al.·Int J Mol Sci
2022Review
SLC39A14 promotes the development of esophageal squamous cell carcinoma through PI3K/Akt/mTOR signaling pathway.
Qu H et al.·Int Immunopharmacol
2025
Pathophysiological studies of aging Slc39a14 knockout mice to assess the progression of manganese-induced dystonia-parkinsonism.
Rodichkin AN et al.·Neurotoxicology
2022
Removal of Toxic Metabolites-Chelation: Manganese Disorders.
Vogt H et al.·J Inherit Metab Dis
2025Review
Forced Overexpression and Knockout Analysis of SLC30A and SLC39A Family Genes Suggests Their Involvement in Establishing Resistance to Cisplatin in Human Cancer Cells.
Kamynina M et al.·Int J Mol Sci
2024
Novel founder intronic variant in SLC39A14 in two families causing Manganism and potential treatment strategies.
Rodan LH et al.·Mol Genet Metab
2018Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
MT1E binds to LncRNA NEAT1 to regulate SLC39A14-mediated ferroptosis in the pathogenesis of aortic dissection.
Xiao C et al.·Exp Cell Res
2026
Peptide‑based therapeutics targeting the SLC39A14‑PIWIL2 fusion in hepatocellular carcinoma.
Shah M et al.·Genomics Inform
2025🔓 Open Access
SLC39A14 is Required for Iron Loading of the Anterior Pituitary of Mice with Genetic Iron Overload.
Olivera J et al.·Biol Trace Elem Res
2025
Metal ion transporter SLC39A14-mediated ferroptosis and glycosylation modulate the tumor immune microenvironment: pan-cancer multi-omics exploration of therapeutic potential.
Chiang YC et al.·Cancer Cell Int
2025🔓 Open Access
Reduction in the hepatocellular carcinoma antioncogene SLC39A14 during the malignant progression of hepatocellular carcinoma.
Guo W et al.·World J Gastrointest Surg
2025🔓 Open Access
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