NCKAP1
protein-codingNCK associated protein 1, the group of SCAR/WAVE complex
Gene summary
Contributes to small GTPase binding activity. Involved in Rac protein signal transduction; positive regulation of Arp2/3 complex-mediated actin nucleation; and positive regulation of lamellipodium assembly. Located in extracellular exosome and focal adhesion. Part of SCAR complex. [provided by Alliance of Genome Resources, Jul 2025]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~129.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: ClinGen
*NCKAP1* encodes a core component of the WAVE complex that regulates neuronal cytoskeletal dynamics. NCKAP1 was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2020 (Guo et al., PMID: 33157009). Both *de novo* and inherited truncating variants have been reported. Common phenotypes in individuals with NCKPA1-related neurodevelopmental disorder include global developmental delay, intellectual disability or learning disabilities, speech-language problems, autism spectrum disorder or autistic features, attention deficit-hyperactivity disorder, and seizures. Additionally, some patients exhibit tall stature, obesity, gastrointestinal disturbances, hearing and visual impairment, and congenital heart defects. In familial cases, the variants segregated with intellectual disability, seizures or variable neuropsychiatric phenotypes, including schizophrenia, psychotic episodes, depression, and severe anxiety. Sixteen variants (5 frameshift, 6 nonsense, 3 canonical splice, and 2 splice region variants shown to lead to exon skipping) reported in 17 probands in 5 publications (PMIDs: 33157009, 36553572, 40551827, 41462819, 41531171) are included in this curation. Nine variants occurred *de novo*, 5 were inherited and 3 were of unknown inheritance. Four of the variants are located in the penultimate or last exon and are not predicted to cause nonsense-mediated decay. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. *NCKAP1* is highly constrained for truncating variants (pLI = 1, LOEUF = 0.2, gnomAD v4.1.1). The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by biochemical function, functional alterations in non-patient cells and a mouse model. Two other genes encoding components of the WAVE regulatory complex, *CYFIP2* and *WASF1*, have been implicated in neurodevelopmental disorders with overlapping features. *Nckap1* (*Nap1*) knock-down in cortical neurons and in mouse embryos resulted in reduced axonal and dendritic growth and branching and retarded neuronal differentiation *in vivo* (PMID:17481396). Nckap1 plays an essential role in facilitating neuronal cytoskeletal changes underlying the differentiation of cortical neurons. In summary, there is definitive evidence supporting the relationship between *NCKPA1* and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 6, 2023. It was reevaluated on June 22, 2026 (SOP Version 12). Although additional cases were added, the classification did not change.
Inheritance Pattern: AD
Disease ID:MONDO:0700092
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0700092
Submitter: PanelApp Australia
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NCKAP1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_013436.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 13 | 1 | 15 | ||
| missense | 3 | 181 | 2 | 186 | ||
| nonsense | 6 | 3 | 2 | 11 | ||
| start loss | 0 | |||||
| frameshift | 4 | 8 | 3 | 15 | ||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 6 | 9 | ||
| Total | 11 | 16 | 193 | 15 | 1 | 236 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_038464.1 | 31 | MANE Select | |
| Ensembl | ENSP00000355348.3 | 31 | MANE Select | |
| RefSeq | NP_001424195.1 | 31 | Standard | |
| RefSeq | NP_001424196.1 | 32 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| nckap1 | Danio rerio | Structure: CaP motoneuron Quality: has fewer parts of type abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Regulation of actin cytoskeleton - Homo sapiens (human)
- Exercise-induced Circadian Regulation
- Regulation of Actin Cytoskeleton
- Signal Transduction
- VEGFA-VEGFR2 Pathway
Biological Process
- cell morphogenesis
- apoptotic process
- central nervous system development
- positive regulation of lamellipodium assembly
- viral process
Molecular Function
- protein binding
- Rac GTPase binding
Cellular Component
- ruffle
- cytosol
- focal adhesion
- integral component of membrane
- lamellipodium
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000360982
- Coding exons
- 32
- Length
- 129744
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.27 | 291 | 581 | 0.501 | 0.0000287 | 7483 |
| Missense (PolyPhen) | 56 | 154.07 | 0.36346 | 2017 | ||
| Synonymous | 0.221 | 194 | 198 | 0.980 | 0.00000984 | 2051 |
| Loss of Function | 7.60 | 0 | 67.2 | 0.00 | 0.00000352 | 850 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Part of the WAVE complex that regulates lamellipodia formation. The WAVE complex regulates actin filament reorganization via its interaction with the Arp2/3 complex. Actin remodeling activity is regulated by RAC1. As component of the WAVE1 complex, required for BDNF-NTRK2 endocytic trafficking and signaling from early endosomes. {ECO:0000250|UniProtKB:P28660}.;
Recessive Scores
- pRec
- 0.186
Intolerance Scores
- LoFtool
- 0.0326
- RVIS EVS
- -1.2
- RVIS percentile EVS
- 5.76
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- E
- Essential (gene trap)
- H
- Indispensability pred.
- E
- Indispensability score
- 0.801
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |