FCHO1

protein-coding

FCH and mu domain containing endocytic adaptor 1, the group of F-BAR domain containing

Gene summary

Enables AP-2 adaptor complex binding activity. Involved in several processes, including T cell receptor signaling pathway; clathrin coat assembly; and clathrin-dependent endocytosis. Located in cytosol; nucleoplasm; and plasma membrane. Is active in clathrin-coated pit. Implicated in primary immunodeficiency disease. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_015122.3

Inheritance

ClinVar variants

P:22U:358B:243

Top phenotype

Immunodeficiency 76

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr19:17,747,718-17,788,568

External References & Databases

Ensembl (ENSG00000130475)

Transcript & Mutation Effects

hg38 • Region Span ~40.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 76STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030898

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency 76STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030898

Submitter: PanelApp Australia

immunodeficiency 76DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0030898

Submitter: ClinGen

*FCHO1* was first reported in relation to autosomal recessive immunodeficiency 76 in 2019 (Calzoni E, et al., 2019, PMID: 30822429). This primary immunologic disorder is characterized by onset of recurrent bacterial, viral, and fungal infections in early childhood. Laboratory studies show T-cell lymphopenia and may show variable B-cell or immunoglobulin abnormalities. Genetic evidence was included in this curation from 8 probands in two publications (PMID: 30822429, PMID: 32098969). The proposed mechanism of disease is loss of function and the reported variants include missense, splice site, frameshift, and nonsense. There is no in vivo evidence of T-cell dysfunction in healthy carriers. More evidence is available in the literature however, the maximum score for genetic evidence was reached. In patients, the absence of functional *FCHO1* results in perturbed clathrin-mediated endocytosis (CME) in several tissues, as well as dysfunctional internalization of transferrin (PMID: 30822429) and the T-cell receptor (PMID: 32098969). Experimentally, this gene-disease relationship is supported by its function as a CME nucleator (PMID: 20448150) and enhanced expression in lymphoid cells (PMID: 30822429), however the relationship between the molecular mechanism of impaired CME and the resulting immunodeficiency requires further elucidation. Functional alteration in patient cells demonstrated defective CME, impaired T-cell proliferation, and increased activation-induced T-cell death, suggesting that defective T-cell proliferation and increased activation-induced cell death, rather than impaired thymic output, are major contributors to the T-cell lymphopenia observed in patients with *FCHO1* deficiency (PMID: 30822429) and FCHO1 knockout cells provide evidence that *FCHO1* plays a role in TCR-dependent T-cell activation (PMID: 32098969). In summary, there is Definitive evidence to support this gene-disease relationship. This has been repeatedly demonstrated in both research and the clinical diagnostic setting and has been upheld over time.

Clinical Genomic Database (CGD)

Immunodeficiency 76AR

Manifestation: Allergy/Immunology/Infectious; Oncologic

Intervention: Allergy/Immunology/Infectious; Oncologic

Rationale: Individuals have been described as affected by early-onset and severe infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Oncologic complications have been described, and awareness may alow early diagnosis and management; HSCT has been described

Refs: 30822429; 32098969

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FCHO1 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 805

not specifiedTotal: 228

FCHO1-related disorderTotal: 10

Immunodeficiency 76Total: 10

Severe congenital neutropeniaTotal: 6

Immunodeficiency with T and B cell lymphopeniaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015122.3. 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			7 clinvar	224 clinvar	1 clinvar	232
missense	2 clinvar		345 clinvar	17 clinvar	1 clinvar	365
nonsense	5 clinvar	1 clinvar				6
start loss						0
frameshift	8 clinvar		3 clinvar			11
splice donor/acceptor (+/-2bp)	4 clinvar	2 clinvar	3 clinvar			9
Total	19	3	358	241	2	623

Highest pathogenic variant AF is 0.0000043368195

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 120 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015122.3	RefSeq	NP_055937.1	26	MANE Select
ENST00000596536.6	Ensembl	ENSP00000470731.1	26	MANE Select
NM_001161357.2	RefSeq	NP_001154829.1	26	Standard
NM_001161358.2	RefSeq	NP_001154830.1	26	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
fcho1	Danio rerio	Structure: whole organism Quality: oblong abnormal

Gene / Model

Organism

Observed Phenotype

fcho1

Danio rerio

Structure: whole organism

Quality: oblong

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
Clathrin-mediated endocytosis
Cargo recognition for clathrin-mediated endocytosis

Biological Process

clathrin coat assembly
membrane organization
clathrin-dependent endocytosis
plasma membrane tubulation

Molecular Function

protein binding
phospholipid binding
microtubule binding
cytoskeletal protein binding
tubulin binding

Cellular Component

nucleoplasm
cytoplasm
cytosol
cytoskeleton
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000594202
Coding exons: 26
Length: 40851
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 125747
p: 0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.40	479	574	0.835	0.0000363	5694
Missense (PolyPhen)		136	176.64	0.76991		1834
Synonymous	0.0710	236	237	0.994	0.0000154	1867
Loss of Function	5.61	7	49.7	0.141	0.00000245	545

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Functions in an early step of clathrin-mediated endocytosis. Has both a membrane binding/bending activity and the ability to recruit proteins essential to the formation of functional clathrin-coated pits. May regulate Bmp signaling by regulating clathrin-mediated endocytosis of Bmp receptors. {ECO:0000269|PubMed:20448150}.;

Recessive Scores

pRec: 0.0981

Intolerance Scores

LoFtool: 0.396
RVIS EVS: -1.1
RVIS percentile EVS: 6.91

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.811

Gene Damage Prediction

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