NDFIP2

Chr 13

Nedd4 family interacting protein 2

Also known as: N4WBP5A

NCBI Gene: 54602 ENSG00000102471 UniProt: Q9NV92

The NDFIP2 protein activates HECT domain-containing E3 ubiquitin ligases and regulates the stability of multiple cellular targets, including potassium channels and cytokine signaling components. Mutations cause autosomal recessive neurodevelopmental disorder with seizures and dysmorphic features, typically presenting in early childhood. The gene shows significant constraint against loss-of-function variants (LOEUF 0.514), indicating intolerance to protein-disrupting mutations.

ResearchSummary from RefSeq, UniProt

Enables WW domain binding activity. Involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Located in several cellular components, including Golgi apparatus; mitochondrion; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Jun 2026]

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

0.51

LOEUF

Multiple*

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

Moderate LoF intolerance

LoF Constraint?

0.51LOEUF

pLI 0.527

Z-score 2.88

OE 0.20 (0.09–0.51)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.62Z-score

OE missense 0.87 (0.76–0.99)

150 obs / 172.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.20 (0.09–0.51)

0≤0.351.4

Missense OE?0.87 (0.76–0.99)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 3 / 15.1Missense obs/exp: 150 / 172.9Syn Z: 0.08

Background carrier burden — how many people carry a rare variant somewhere in NDFIP2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

473 rare PASS variants

Rare truncating (LoF)

1 in 3,700

59 rare PASS variants

Rare synonymous (reference)

1 in 320

187 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NDFIP2. 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 130	1 in 4,400
South Asian	~43k	1 in 130	1 in 5,700
Remaining (unassigned)	~30k	1 in 160	1 in 5,900
European (Finnish)	~27k	1 in 330	≈ 1 in 6,900
Admixed American	~22k	1 in 120	1 in 1,800
African / African American	~21k	1 in 120	1 in 2,300
East Asian	~20k	1 in 87	1 in 730
Ashkenazi Jewish	~13k	1 in 390	none seen
Middle Eastern	~2,883	1 in 200	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): 5 of 7 coding exons well covered in gnomAD exomes; exons 6, 7 marginal. Genomes: all 7.? see exons ↓