NIPA1

Chr 15AD

NIPA magnesium transporter 1

Also known as: FSP3, SLC57A1, SPG6

NCBI Gene: 123606 ENSG00000170113 UniProt: Q7RTP0 OMIM: 608145

This gene encodes a magnesium transporter that associates with early endosomes and the cell surface in neuronal and epithelial cells. Mutations cause autosomal dominant spastic paraplegia 6, a hereditary spastic paraplegia affecting the corticospinal tracts and resulting in progressive lower limb spasticity and weakness. The gene shows tolerance to loss-of-function variants (pLI 0.006, LOEUF 1.04), and comprehensive clinical information is available in GeneReviews.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 1.041 OMIM phenotype

Clinical Summary— NIPA1

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

142 unique Pathogenic / Likely Pathogenic· 147 VUS of 398 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NIPA1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

1.04LOEUF

pLI 0.006

Z-score 1.49

OE 0.49 (0.26–1.04)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint

1.94Z-score

OE missense 0.60 (0.51–0.70)

110 obs / 184.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.49 (0.26–1.04)

0≤0.351.4

Missense OE0.60 (0.51–0.70)

0≤0.61.4

Synonymous OE1.18

0≤1.21.6

LoF obs/exp: 5 / 10.1Missense obs/exp: 110 / 184.1Syn Z: -1.32

0.6937th %ile

GOF

0.76top 25%

LOF

0.2483th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNWe report discovery of a dominant negative mutation in the NIPA1 gene in a kindred with autosomal dominant HSP (ADHSP), linked to chromosome 15q11-q13 (SPG6 locus); and precisely the same mutation in an unrelated kindred with ADHSP that was too small for meaningful linkage analysis.PMID:14508710

GOFHereditary spastic paraplegia-associated mutations in the NIPA1 gene and its Caenorhabditis elegans homolog trigger neural degeneration in vitro and in vivo through a gain-of-function mechanism.PMID:19091982

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