AP1G1

protein-coding

adaptor related protein complex 1 subunit gamma 1, the group of Clathrin/coatomer adaptor, adaptin-like, N-terminal domain containing|Adaptor related protein complex 1|Small nucleolar RNA protein coding host genes

Gene summary

Adaptins are important components of clathrin-coated vesicles transporting ligand-receptor complexes from the plasma membrane or from the trans-Golgi network to lysosomes. The adaptin family of proteins is composed of four classes of molecules named alpha, beta-, beta prime- and gamma- adaptins. Adaptins, together with medium and small subunits, form a heterotetrameric complex called an adaptor, whose role is to promote the formation of clathrin-coated pits and vesicles. The protein encoded by this gene is a gamma-adaptin protein and it belongs to the adaptor complexes large subunits family. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

CLAPG1
ADTG

MANE transcript

NM_001128.6

Inheritance

SD, AR, AD

ClinVar variants

P:26U:156B:45

Top phenotype

Usmani-Riazuddin syndrome, autosomal dominant

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr16:71,729,000-71,809,201

External References & Databases

Ensembl (ENSG00000166747)

Transcript & Mutation Effects

hg38 • Region Span ~80.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Usmani-Riazuddin syndrome, autosomal recessiveLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859196

Submitter: G2P

Usmani-Riazuddin syndrome, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859196

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*AP1G1* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2021 (Usmani et al., PMID: 34102099). Of note, *AP1G1* has also been implicated in autosomal recessive complex neurodevelopmental disorder (Usmani-Riazuddin syndrome, autosomal recessive). The split curation for Usmani-Riazuddin syndrome, autosomal recessive, is assessed separately. *AP1G1*-related autosomal dominant complex neurodevelopmental disorder (also known as Usmani-Riazuddin syndrome, autosomal dominant) is characterized by global developmental delay with variably impaired intellectual development, speech delay, and behavioral abnormalities, including aggression, hyperactivity, and autism spectrum disorder or autistic features. Additional common features include seizures, hypotonia, and distal limb anomalies. Five de novo missense variants and three de novo loss-of-function variants have been reported in nine unrelated patients (PMID: 34102099). This gene-disease relationship is also supported by experimental evidence. AP1G1 interacts with other adaptor protein complex 1 (AP-1) proteins, AP1S1/AP1S2, which have been definitively implicated in neurodevelopmental disorders. AP complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. In summary, there is strong evidence to support this gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 2, 2022 (SOP Version 9).

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

*AP1G1* was first reported in relation to autosomal recessive complex neurodevelopmental disorder in 2021 (Usmani et al., PMID: 34102099). Of note, *AP1G1* has also been implicated in autosomal dominant complex neurodevelopmental disorder (Usmani-Riazuddin syndrome, autosomal dominant). The split curation for Usmani-Riazuddin syndrome, autosomal dominant, is assessed separately. *AP1G1*-related autosomal recessive complex neurodevelopmental disorder (also known as Usmani-Riazuddin syndrome, autosomal recessive) has been reported in three affected individuals from two unrelated consanguineous families carrying homozygous missense variants functionally characterized in cell culture and zebrafish models (PMID: 34102099). Common features in affected individuals included global developmental delay, hypotonia, speech delay, moderately to severely impaired intellectual development, and spasticity. This gene-disease relationship is also supported by experimental evidence. AP1G1 interacts with other adaptor protein complex 1 (AP-1) proteins, AP1S1/AP1S2, which have been definitively implicated in neurodevelopmental disorders. AP complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 2, 2022 (SOP Version 9).

Usmani-Riazuddin syndrome, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859174

Submitter: Labcorp Genetics (formerly Invitae)

Usmani-Riazuddin syndrome, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859174

Submitter: G2P

Clinical Genomic Database (CGD)

Usmani-Riazuddin syndrome, autosomal dominantAD/AR

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: 34102099

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AP1G1 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 83

not providedTotal: 81

Usmani-Riazuddin syndrome, autosomal dominantTotal: 31

not specifiedTotal: 22

AP1G1-related disorderTotal: 18

Usmani-Riazuddin syndrome, autosomal recessiveTotal: 6

Neurodevelopmental disorderTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001128.6. 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		1 clinvar	4 clinvar	14 clinvar		19
missense	3 clinvar	3 clinvar	129 clinvar	31 clinvar		166
nonsense	5 clinvar	3 clinvar	8 clinvar			16
start loss						0
frameshift	5 clinvar	2 clinvar	7 clinvar			14
splice donor/acceptor (+/-2bp)	2 clinvar	2 clinvar	8 clinvar			12
Total	15	11	156	45	0	227

Highest pathogenic variant AF is 0.000008055591

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 55 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001128.6	RefSeq	NP_001119.3	22	MANE Select
ENST00000299980.9	Ensembl	ENSP00000299980.4	22	MANE Select
NM_001030007.2	RefSeq	NP_001025178.1	23	Standard
ENST00000393512.7	Ensembl	ENSP00000377148.3	23	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ap1g1	Danio rerio	Structure: blood cell Quality: mislocalised abnormal

Gene / Model

Organism

Observed Phenotype

ap1g1

Danio rerio

Structure: blood cell

Quality: mislocalised

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)
Golgi Associated Vesicle Biogenesis
Lysosome Vesicle Biogenesis
Clathrin derived vesicle budding
Disease

Biological Process

intracellular protein transport
antigen processing and presentation of exogenous peptide antigen via MHC class II
melanosome organization
endosome to melanosome transport
positive regulation of natural killer cell degranulation

Molecular Function

transporter activity
protein binding
Rab GTPase binding
kinesin binding
GTP-dependent protein binding

Cellular Component

Golgi membrane
cytoplasm
lysosomal membrane
Golgi apparatus
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000393512
Coding exons: 23
Length: 80192
Individuals with no LoFs: 125742
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125747
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.98	277	456	0.607	0.0000242	5382
Missense (PolyPhen)		47	158.58	0.29637		1872
Synonymous	-0.303	165	160	1.03	0.00000796	1605
Loss of Function	6.05	5	52.2	0.0959	0.00000333	569

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000063	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Subunit of clathrin-associated adaptor protein complex 1 that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes. The AP complexes mediate both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules.;

Recessive Scores

pRec: 0.119

Intolerance Scores

LoFtool: 0.247
RVIS EVS: -0.76
RVIS percentile EVS: 13.45

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.961

Gene Damage Prediction

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