NPIPB4

Chr 16

nuclear pore complex interacting protein family member B4

Also known as: 61E3.4

NCBI Gene: 440345 ENSG00000185864 UniProt: C9JG80

NPIPB4 encodes a protein predicted to be located in cellular membranes, though its specific function remains poorly characterized. The gene shows relatively low constraint against loss-of-function variants (pLI 0.18, LOEUF 0.96), suggesting tolerance to protein-disrupting mutations. No definitive disease associations have been established for NPIPB4 mutations in current medical literature.

ResearchSummary from RefSeq

Predicted to be located in membrane. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.96

Clinical Summary— NPIPB4

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.

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ClinVar Variants

2 total variants — no pathogenic classifications of 2 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?

0.96LOEUF

pLI 0.183

Z-score 1.64

OE 0.31 (0.12–0.96)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.45Z-score

OE missense 1.11 (0.97–1.26)

157 obs / 142.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.31 (0.12–0.96)

0≤0.351.4

Missense OE?1.11 (0.97–1.26)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 2 / 6.5Missense obs/exp: 157 / 142.0Syn Z: 0.04

This gene — mechanism propensity

0.84top 10%

GOF

0.93top 5%

LOF

0.3746th %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

2 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Benign2

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	0	0
Likely Benign	2	2
Benign	0	0
Total	2	2

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

View in ClinVar →

52 pathogenic / likely-pathogenic (of 100) ClinVar copy-number / structural variants overlap NPIPB4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →