NPIPA5

Chr 16

nuclear pore complex interacting protein family member A5

Also known as: NPIP

NCBI Gene: 100288332 ENSG00000183793 UniProt: E9PKD4

The NPIPA5 protein is a nuclear pore complex-interacting protein involved in nucleocytoplasmic transport regulation. Mutations cause autosomal recessive intellectual disability with developmental delay and seizures. This gene shows low constraint against loss-of-function variants, consistent with a recessive inheritance pattern.

Research

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.86

Clinical Summary— NPIPA5

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Population Constraint (gnomAD)

Low constraint (pLI 0.11) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

1 VUS of 5 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?

1.86LOEUF

pLI 0.108

Z-score 0.27

OE 0.75 (0.23–1.86)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.95Z-score

OE missense 1.62 (1.40–1.86)

128 obs / 79.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.75 (0.23–1.86)

0≤0.351.4

Missense OE?1.62 (1.40–1.86)

0≤0.61.4

Synonymous OE?1.42

0≤1.21.6

LoF obs/exp: 1 / 1.3Missense obs/exp: 128 / 79.2Syn Z: -1.92

This gene — mechanism propensity

0.76top 25%

GOF

0.78top 25%

LOF

0.3842th %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

5 submitted variants in ClinVar

ClinVar

Classification Summary

VUS1

Likely Benign2

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	1	0	1
Likely Benign	1	1	2
Benign	0	0	0
Total	2	1	3

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

View in ClinVar →

159 pathogenic / likely-pathogenic (of 276) ClinVar copy-number / structural variants overlap NPIPA5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →