NXPH1

Chr 7

neurexophilin 1

Also known as: NPH1, Nbla00697

NCBI Gene: 30010 ENSG00000122584 UniProt: P58417 OMIM: 604639

The protein is a secreted signaling molecule that forms tight complexes with alpha-neurexins to promote adhesion between dendrites and axons. Mutations cause autosomal recessive neurodevelopmental disorders including developmental and epileptic encephalopathy and intellectual disability with autism spectrum features. The gene shows moderate constraint against loss-of-function variants, suggesting some tolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

This gene is a member of the neurexophilin family and encodes a secreted protein with a variable N-terminal domain, a highly conserved, N-glycosylated central domain, a short linker region, and a cysteine-rich C-terminal domain. This protein forms a very tight complex with alpha neurexins, a group of proteins that promote adhesion between dendrites and axons. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.62

Clinical Summary— NXPH1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.20) despite low pLI — interpret in context.

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ClinVar Variants

38 VUS of 42 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?

0.62LOEUF

pLI 0.484

Z-score 2.38

OE 0.20 (0.08–0.62)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.27Z-score

OE missense 0.94 (0.81–1.08)

134 obs / 143.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.20 (0.08–0.62)

0≤0.351.4

Missense OE?0.94 (0.81–1.08)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 2 / 10.2Missense obs/exp: 134 / 143.0Syn Z: -0.91

This gene — mechanism propensity

0.6259th %ile

GOF

0.5563th %ile

LOF

0.54top 25%

The highest-scoring mechanism for this gene is dominant-negative.

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

42 submitted variants in ClinVar

ClinVar

Classification Summary

VUS38

Likely Benign1

Benign2

VUS

Likely Benign

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	38	0	38
Likely Benign	0	1	1
Benign	0	2	2
Total	38	3	41

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 45) ClinVar copy-number / structural variants overlap NXPH1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →