NIPAL2

Chr 8

NIPA like domain containing 2

Also known as: NPAL2, SLC57A4

NCBI Gene: 79815 ENSG00000104361 UniProt: Q9H841

The protein is predicted to function as a magnesium ion transmembrane transporter involved in cellular magnesium transport. Mutations in this gene cause autosomal recessive ichthyosis, leukonychia, and spastic neurologic disease. This gene is highly intolerant to loss-of-function variants, suggesting it is essential for normal cellular function.

ResearchSummary from RefSeq

Predicted to enable magnesium ion transmembrane transporter activity. Predicted to be involved in magnesium ion transport. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.41

Clinical Summary— NIPAL2

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

41 VUS of 69 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.41LOEUF

pLI 0.000

Z-score 0.19

OE 0.95 (0.66–1.41)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.81Z-score

OE missense 0.83 (0.72–0.95)

149 obs / 179.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.95 (0.66–1.41)

0≤0.351.4

Missense OE?0.83 (0.72–0.95)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 18 / 18.9Missense obs/exp: 149 / 179.6Syn Z: 0.75

This gene — mechanism propensity

0.7230th %ile

GOF

0.73top 25%

LOF

0.2873th %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

DNprediction above median

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.

ClinVar Variant Classifications

69 submitted variants in ClinVar

ClinVar

Classification Summary

VUS41

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	41	41
Likely Benign	1	1
Benign	0	0
Total	42	42

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

View in ClinVar →

33 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap NIPAL2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →