NIPA1

Chr 15

NIPA magnesium transporter 1

Also known as: FSP3, SLC57A1, SPG6

NCBI Gene: 123606 ENSG00000170113 UniProt: Q7RTP0

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 ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a magnesium transporter that associates with early endosomes and the cell surface in a variety of neuronal and epithelial cells. This protein may play a role in nervous system development and maintenance. Multiple transcript variants encoding different isoforms have been found for this gene. Mutations in this gene have been associated with autosomal dominant spastic paraplegia 6. [provided by RefSeq, Nov 2008]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.04

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

6 unique Pathogenic / Likely Pathogenic· 197 VUS of 386 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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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.49 (0.26–1.04)

0≤0.351.4

Missense OE?0.60 (0.51–0.70)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

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

This gene — mechanism propensity

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.1

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.2

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

References

ClinVar Variant Classifications

386 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic1

VUS197

Likely Benign98

Benign63

Conflicting19

Pathogenic

Likely Pathogenic

197

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	4	1	0	5
Likely Pathogenic	0	0	1	0	1
VUS	1	111	82	3	197
Likely Benign	0	8	36	54	98
Benign	0	3	57	3	63
Conflicting	—				19
Total	1	126	177	60	383

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

View in ClinVar →

215 pathogenic / likely-pathogenic (of 347) ClinVar copy-number / structural variants overlap NIPA1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →