NPAS4

Chr 11

neuronal PAS domain protein 4

Also known as: Le-PAS, NXF, PASD10, bHLHe79

NCBI Gene: 266743 ENSG00000174576 UniProt: Q8IUM7

NPAS4 encodes a transcription factor that regulates excitatory-inhibitory balance within neural circuits and is required for contextual memory formation and synaptic plasticity. Mutations cause autosomal dominant developmental and epileptic encephalopathy with developmental delay, intellectual disability, and seizures typically beginning in infancy or early childhood. The gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to be pathogenic.

ResearchSummary from RefSeq, UniProt

NXF is a member of the basic helix-loop-helix-PER (MIM 602260)-ARNT (MIM 126110)-SIM (see SIM2; MIM 600892) (bHLH-PAS) class of transcriptional regulators, which are involved in a wide range of physiologic and developmental events (Ooe et al., 2004 [PubMed 14701734]).[supplied by OMIM, Mar 2008]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.32

LOEUF· LoF intol.

LOF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.32LOEUF

pLI 0.973

Z-score 4.28

OE 0.14 (0.07–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.52Z-score

OE missense 0.80 (0.73–0.87)

348 obs / 437.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.14 (0.07–0.32)

0≤0.351.4

Missense OE?0.80 (0.73–0.87)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 4 / 28.8Missense obs/exp: 348 / 437.7Syn Z: -0.97

Background carrier burden — how many people carry a rare variant somewhere in NPAS4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 89

967 rare PASS variants

Rare truncating (LoF)

1 in 12,000

22 rare PASS variants

Rare synonymous (reference)

1 in 92

477 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NPAS4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 110	1 in 25,000
South Asian	~43k	1 in 91	1 in 1,700
Remaining (unassigned)	~30k	1 in 79	≈ 1 in 9,900
European (Finnish)	~27k	1 in 220	none seen
Admixed American	~22k	1 in 72	none seen
African / African American	~21k	1 in 83	≈ 1 in 10,000
East Asian	~20k	1 in 82	none seen
Ashkenazi Jewish	~13k	1 in 770	≈ 1 in 6,100
Middle Eastern	~2,884	1 in 85	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 8 coding exons well covered in gnomAD exomes and genomes.? see exons ↓