Curation ALS1 NIPA1

Gene NIPA

Disease ALS1

Inheritance AD

Score

2 + 1 = 3 / 18

Genetic + experimental = total

Classification

Disputed

Refuted

Moderate

Definitive

Last Updated 06/06/2025

Pubs Reviewed 3

Publication Span 2.33 years

Publication Interval 2.33 years

Curator(s) Macayla Weiner, Laurel Hiatt, Harriet Dashnow

Description

The NIPA1 exon 1 GCG/polyalanine repeat has been reported as an ALS risk or modifier locus, with some European cohorts showing enrichment or survival effects for long alleles (≥9 or >8 GCG repeats), whereas African-ancestry and broader Project MinE STR studies did not confirm an ALS susceptibility or age-at-onset association. The evidence is conflicting and largely association-based, with limited direct locus-specific evidence, supporting the disputed classification. The evidence does not currently support a Mendelian association between the NIPA1 repeat and ALS.

All criTRia Curations Locus Page

Genetic evidence

Total: 2

Per page

Category	Type	Citation	Score	Details
Singular Evidence	Probands	PMID:31286297	0	6 patients with the NIPA1 expansion, co-occuring with a C9orf72 expansion. The source reports cohort-level NIPA1 repeat genotyping but does not describe individual NIPA1-expanded ALS probands with phenotype, family, or functional details suitable for singular proband scoring. Therefore, a score of 0 is assigned for this evidence.
Collective Evidence	Computational	PMID:34179866	0	ExpansionHunter WGS analysis of Southern African ALS cases and African controls found similar NIPA1 GCG-repeat distributions (p = 0.67); long alleles (≥9 GCG repeats) were rare in Africans and not associated with ALS, while 9–10-repeat alleles were more common in European than African controls (6% vs 0.4%, p = 0.016). Score of 0 assigned as this evidence does not support an association between the NIPA1 repeat and ALS.
Statistics	Case-control data	PMID:31286297	2	Project MinE STR analysis found NIPA1 ≥9-repeat alleles in 232 ALS cases (4.6%) and 78 controls (4.6%), with no significant ALS susceptibility association; NIPA1 showed only a nominal survival association. They used two methods of variant detection.

Experimental evidence

Total: 1

Per page

Category	Type	Citation	Score	Details
Function	Protein interaction	PMID:30342764	1	Authors found altered protein to protein interactions and sequesteration of RNA-binding protein.

Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.