TRAPPC4

protein-coding

trafficking protein particle complex subunit 4, the group of Trafficking protein particle complex subunits|MicroRNA protein coding host genes

Gene summary

Involved in autophagy and endoplasmic reticulum to Golgi vesicle-mediated transport. Part of TRAPP complex. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_016146.6

Inheritance

AR, AD

ClinVar variants

P:2U:45B:4

Top phenotype

Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy

gnomAD constraint

pLI —, LoF o/e 0.85

Max pathogenic AF

—

Genomic locus

chr11:119,018,763-119,025,454

External References & Databases

Ensembl (ENSG00000196655)

Transcript & Mutation Effects

hg38 • Region Span ~6.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with epilepsy, spasticity, and brain atrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032894

Submitter: PanelApp Australia

syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: Orphanet

neurodevelopmental disorder with epilepsy, spasticity, and brain atrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032894

Submitter: G2P

neurodevelopmental disorder with epilepsy, spasticity, and brain atrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032894

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with epilepsy, spasticity, and brain atrophyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032894

Submitter: Ambry Genetics

neurodevelopmental disorder with epilepsy, spasticity, and brain atrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032894

Submitter: ClinGen

The TRAPPC4 gene is located on chromosome 11 at 11q23.3 and encodes a highly conserved component of the TRAPP (TRAfficking Protein Particle) complex, which regulates key intracellular vesicular trafficking events, including secretion, and is involved in autophagy. TRAPPC4 was first reported in relation to autosomal recessive neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (NEDESBA) in 2020 (Van Bergen et al., PMID: 31794024). NEDESBA has features of severe global developmental delay evident in infancy, with early-onset seizures, and hypotonia. Some individuals may present with hearing loss and vision issues. The condition is mainly caused by a splicing variant; eight affected probands from eight families with this variant are included in this curation (PMIDs: 31794024, 32901138). Two missense variants more recently found in three probands in two affected families are also included in this curation (PMID: 34878169). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by experimental evidence including rescue, interaction, and functional alteration evidence (PMIDs: 20972447, 31794024). The splicing variant was shown to inhibit autophagy through a functional alteration study in patient fibroblasts, and function in patient fibroblasts cells could be rescued by introducing TRAPPC4. In addition, a study in yeast demonstrated that the protein is essential for a TRAPP complex, which contains nine subunits and is associated with intellectual disability. In summary, there is definitive evidence supporting the relationship between TRAPPC4 and autosomal recessive NEDESBA. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 12/6/23 (SOP Version 9).

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophyAR

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 31794024

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRAPPC4 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 34

not providedTotal: 13

Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophyTotal: 11

TRAPPC4-related disorderTotal: 2

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

Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomaliesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016146.6. 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	2 clinvar	2 clinvar	6
missense		1 clinvar	40 clinvar			41
nonsense						0
start loss						0
frameshift		1 clinvar	1 clinvar			2
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	2	45	2	2	51

Highest pathogenic variant AF is 0.00038454466

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016146.6	RefSeq	NP_057230.1	5	MANE Select
ENST00000533632.6	Ensembl	ENSP00000436005.1	5	MANE Select
NM_001318486.2	RefSeq	NP_001305415.1	3	Standard
NM_001318488.2	RefSeq	NP_001305417.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
Post-translational protein modification
Metabolism of proteins
Extracellular matrix organization

Biological Process

endoplasmic reticulum to Golgi vesicle-mediated transport
dendrite development
COPII vesicle coating

Molecular Function

protein binding
Rab guanyl-nucleotide exchange factor activity

Cellular Component

Golgi membrane
endoplasmic reticulum
Golgi stack
cytosol
synaptic vesicle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000533632
Coding exons: 5
Length: 7023
Individuals with no LoFs: 125711
Homozygous LoFs: 0
Heterozygous LoFs: 36
Defined: 125747
p: 0.000143

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.428	106	119	0.890	0.00000526	1407
Missense (PolyPhen)		36	43.975	0.81864		550
Synonymous	-2.49	69	47.2	1.46	0.00000218	446
Loss of Function	0.448	9	10.6	0.851	5.49e-7	116

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00012	0.00012	rare
South Asian	0.00026	0.00026	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role in vesicular transport from endoplasmic reticulum to Golgi.;

Recessive Scores

pRec: 0.145

Intolerance Scores

LoFtool: 0.580
RVIS EVS: -0.27
RVIS percentile EVS: 33.97

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.842

Gene Damage Prediction

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