SLC39A14

Chr 8ADAR

solute carrier family 39 member 14

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

NCBI Gene: 23516 ENSG00000104635 UniProt: Q15043 OMIM: 608736

This protein is a divalent metal transporter that mediates cellular uptake of manganese, zinc, and iron, functioning as a critical regulator of systemic metal homeostasis including manganese transport across the blood-brain barrier and intestinal absorption. Mutations cause hypermanganesemia with dystonia 2 and hyperostosis cranialis interna, both involving early-onset movement disorders with abnormal metal accumulation. The gene shows both autosomal dominant and autosomal recessive inheritance patterns and is moderately constrained against loss-of-function variants (LOEUF 0.554).

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.552 OMIM phenotypes

Clinical Summary— SLC39A14

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

📋

ClinVar Variants

14 unique Pathogenic / Likely Pathogenic· 95 VUS of 286 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — SLC39A14

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

1.92Z-score

OE missense 0.68 (0.60–0.77)

194 obs / 285.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.26 (0.14–0.55)

0≤0.351.4

Missense OE?0.68 (0.60–0.77)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 5 / 19.0Missense obs/exp: 194 / 285.1Syn Z: 0.62

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSLC39A14-related early onset dystonia parkinsonismLOFAR

This gene — mechanism propensity

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

0.7229th %ile

GOF

0.75top 25%

LOF

0.2969th %ile

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

286 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic5

VUS95

Likely Benign116

Benign40

Conflicting6

Pathogenic

Likely Pathogenic

VUS

116

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	5	0	0	9
Likely Pathogenic	2	2	1	0	5
VUS	5	84	4	2	95
Likely Benign	0	8	35	73	116
Benign	0	3	28	9	40
Conflicting	—				6
Total	11	102	68	84	271

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

View in ClinVar →

82 pathogenic / likely-pathogenic (of 100) ClinVar copy-number / structural variants overlap SLC39A14 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →