NIPA2

Chr 15

NIPA magnesium transporter 2

Also known as: SLC57A2

NCBI Gene: 81614 ENSG00000140157 UniProt: Q8N8Q9 OMIM: 608146

The protein functions as a selective magnesium transporter and is highly constrained against loss-of-function variants (pLI=0.92, LOEUF=0.38). Mutations cause autosomal recessive childhood-onset spastic paraplegia with progressive lower limb spasticity and weakness. The gene is located in the Prader-Willi syndrome deletion region on chromosome 15, though NIPA2 mutations cause a distinct neurological phenotype from Prader-Willi syndrome.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a possible magnesium transporter. This gene is located adjacent to the imprinted domain in the Prader-Willi syndrome deletion region of chromosome 15. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 3, 7 and 21.[provided by RefSeq, May 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.38

Clinical Summary— NIPA2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.92). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 55 VUS of 108 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.38LOEUF

pLI 0.921

Z-score 3.02

OE 0.08 (0.03–0.38)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.22Z-score

OE missense 0.96 (0.85–1.08)

187 obs / 195.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.08 (0.03–0.38)

0≤0.351.4

Missense OE?0.96 (0.85–1.08)

0≤0.61.4

Synonymous OE?1.31

0≤1.21.6

LoF obs/exp: 1 / 12.5Missense obs/exp: 187 / 195.8Syn Z: -2.11

This gene — mechanism propensity

0.5868th %ile

GOF

0.7028th %ile

LOF

0.4136th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). 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

LOFLOEUF 0.38

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.

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

ClinVar Variant Classifications

108 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic2

VUS55

Likely Benign14

Benign25

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	1
Likely Pathogenic	1	1	0	2
VUS	50	5	0	55
Likely Benign	4	5	5	14
Benign	2	21	2	25
Total	57	33	7	97

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

View in ClinVar →

215 pathogenic / likely-pathogenic (of 342) ClinVar copy-number / structural variants overlap NIPA2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →