NCKAP1L

protein-coding

NCK associated protein 1 like

Gene summary

This gene encodes a member of the HEM family of tissue-specific transmembrane proteins which are highly conserved from invertebrates through mammals. This gene is only expressed in hematopoietic cells. The encoded protein is a part of the Scar/WAVE complex which plays an important role in regulating cell shape in both metazoans and plants. Alternatively spliced transcript variants encoding different isoforms have been found.[provided by RefSeq, May 2010]

Previous symbols:

HEM1

MANE transcript

NM_005337.5

Inheritance

ClinVar variants

P:14U:183B:187

Top phenotype

Immunodeficiency 72 with autoinflammation and lymphoproliferation

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr12:54,497,752-54,548,243

External References & Databases

Ensembl (ENSG00000123338)

Transcript & Mutation Effects

hg38 • Region Span ~50.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 72 with autoinflammationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033551

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency 72 with autoinflammationMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0033551

Submitter: ClinGen

*NKACP1*L was first reported in relation to autosomal recessive immunodeficiency 72 with autoinflammation in 2020 simultaneously by three separate authors (PMIDs: 32646852, 32647003, 32766723). Patients reported with this disorder can have recurrent bacterial infections, antibody abnormalities, lymphoproliferation, atopy, autoimmune disease and haemophagocytic lymphohistiocytosis. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Seven missense variants have been reported in nine probands in three publications are included in this curation. The heterozygous parents all appear unaffected. The mechanism of pathogenicity appears to be loss of function. NKACP1L encodes for HEM-1, a haematopoietic linage-restricted protein. A review on the function of HEM-1 can be found in PMID: 3902667. Experimental data includes functional studies (PMIDs: 32646852, 32647003, 32766723), mouse model (PMID: 32646852) and rescue in cultured cell lines (PMIDs: 32646852, 32647003). More experimental evidence is available in the literature, but the maximum score for genetic evidence experimental evidence (6 pts.) has been reached. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen PIRD GCEP on the meeting date 9th of June 2026 (SOP Version 12). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen PIRD GCEP on the meeting date 9th of June 2026 (SOP Version 12).

immunodeficiency diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0021094

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Immunodeficiency 72 with autoinflammation and lymphoproliferationAR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: The condition can involve early-onset and severe infections, as well as other immunologic manifestations, and awareness may allow early and aggressive treatment of infections; Medical management of autoimmune disease (with immunomodulatory agents) has been described as beneficial in some individuals

Refs: 32647003

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NCKAP1L variants in ClinVar

5 Conditions Cataloged

not providedTotal: 459

not specifiedTotal: 157

Immunodeficiency 72 with autoinflammationTotal: 17

NCKAP1L-related disorderTotal: 14

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005337.5. 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			2 clinvar	170 clinvar	5 clinvar	177
missense	2 clinvar	8 clinvar	171 clinvar	12 clinvar		193
nonsense			4 clinvar			4
start loss		1 clinvar				1
frameshift		1 clinvar	2 clinvar			3
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	4 clinvar			6
Total	3	11	183	182	5	384

Highest pathogenic variant AF is 0.00006517022

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005337.5	RefSeq	NP_005328.2	31	MANE Select
ENST00000293373.11	Ensembl	ENSP00000293373.6	31	MANE Select
NM_001184976.2	RefSeq	NP_001171905.1	30	Standard
ENST00000545638.2	Ensembl	ENSP00000445596.2	30	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Regulation of actin cytoskeleton - Homo sapiens (human)
Hematopoietic Stem Cell Differentiation
Microglia Pathogen Phagocytosis Pathway
TYROBP Causal Network
Neutrophil degranulation

Biological Process

cell morphogenesis
B cell homeostasis
myeloid cell homeostasis
chemotaxis
cell migration

Molecular Function

GTPase activator activity
protein binding
protein kinase activator activity
protein-containing complex binding
Rac GTPase binding

Cellular Component

cytosol
plasma membrane
integral component of plasma membrane
membrane
secretory granule membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000293373
Coding exons: 31
Length: 46232
Individuals with no LoFs: 125707
Homozygous LoFs: 0
Heterozygous LoFs: 41
Defined: 125748
p: 0.000163

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.48	456	631	0.723	0.0000341	7438
Missense (PolyPhen)		134	217.54	0.61597		2504
Synonymous	0.0300	229	230	0.997	0.0000114	2171
Loss of Function	5.88	13	63.6	0.204	0.00000336	730

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0	0.0	absent
Finnish	0.00037	0.00037	rare
European (Non-Finnish)	0.00023	0.00023	rare
South Asian	0.00013	0.00013	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Essential hematopoietic-specific regulator of the actin cytoskeleton (Probable). Controls lymphocyte development, activation, proliferation and homeostasis, erythrocyte membrane stability, as well as phagocytosis and migration by neutrophils and macrophages (PubMed:16417406, PubMed:17696648). Component of the WAVE2 complex which signals downstream of RAC to stimulate F- actin polymerization. Required for stabilization and/or translation of the WAVE2 complex proteins in hematopoietic cells (By similarity). Exhibits complex cycles of activation and inhibition to generate waves of propagating the assembly with actin (PubMed:16417406). Also involved in mechanisms WAVE- independent to regulate myosin and actin polymerization during neutrophil chemotaxis (PubMed:17696648). {ECO:0000250|UniProtKB:Q8K1X4, ECO:0000269|PubMed:16417406, ECO:0000269|PubMed:17696648, ECO:0000303|PubMed:20969869}.;

Recessive Scores

pRec: 0.105

Intolerance Scores

LoFtool: 0.664
RVIS EVS: -0.46
RVIS percentile EVS: 23.69

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.909

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium