APH1A

protein-coding

aph-1 homolog A, gamma-secretase subunit

Gene summary

This gene encodes a component of the gamma secretase complex that cleaves integral membrane proteins such as Notch receptors and beta-amyloid precursor protein. The gamma secretase complex contains this gene product, or the paralogous anterior pharynx defective 1 homolog B (APH1B), along with the presenilin, nicastrin, and presenilin enhancer-2 proteins. The precise function of this seven-transmembrane-domain protein is unknown though it is suspected of facilitating the association of nicastrin and presenilin in the gamma secretase complex as well as interacting with substrates of the gamma secretase complex prior to their proteolytic processing. Polymorphisms in a promoter region of this gene have been associated with an increased risk for developing sporadic Alzheimer's disease. Alternative splicing results in multiple protein-coding and non-protein-coding transcript variants. [provided by RefSeq, Aug 2011]

MANE transcript

NM_001077628.3

Inheritance

—

ClinVar variants

U:30B:1

Top phenotype

APH1A-related disorder

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr1:150,265,399-150,269,580

External References & Databases

Ensembl (ENSG00000117362)

Transcript & Mutation Effects

hg38 • Region Span ~4.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to APH1A variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 21

APH1A-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001077628.3. 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						0
missense			25 clinvar			25
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			4 clinvar	1 clinvar		5
Total	0	0	30	1	0	31

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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_001077628.3	RefSeq	NP_001071096.1	7	MANE Select
ENST00000369109.8	Ensembl	ENSP00000358105.3	7	MANE Select
NM_001243771.2	RefSeq	NP_001230700.1	5	Standard
NM_001243772.2	RefSeq	NP_001230701.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Alzheimer,s disease - Homo sapiens (human)
Notch signaling pathway - Homo sapiens (human)
NOTCH-Ncore
Alzheimers Disease
Notch Signaling Pathway

Biological Process

metanephros development
membrane protein ectodomain proteolysis
Notch signaling pathway
Notch receptor processing
protein processing

Molecular Function

endopeptidase activity
protein binding

Cellular Component

mitochondrion
endoplasmic reticulum
endoplasmic reticulum membrane
Golgi apparatus
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000369109
Coding exons: 7
Length: 4177
Individuals with no LoFs: 123956
Homozygous LoFs: 15
Heterozygous LoFs: 821
Defined: 124792
p: 0.00336

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.03	86	158	0.545	0.00000852	1670
Missense (PolyPhen)		20	59.097	0.33843		668
Synonymous	0.514	59	64.2	0.918	0.00000324	584
Loss of Function	2.97	2	14.0	0.143	7.64e-7	144

Population LoF Frequency

Population	CAF	p-value	Status
African	0.051	0.050	notable
Latino/Admixed American	0.0016	0.0016	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000080	0.000079	rare
South Asian	0.00030	0.00029	rare
Other	0.00083	0.00082	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Non-catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:12297508, PubMed:12522139, PubMed:12763021, PubMed:12679784, PubMed:25043039, PubMed:26280335). Required for normal gamma- secretase assembly (PubMed:12522139, PubMed:12471034, PubMed:12763021, PubMed:19369254). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable). {ECO:0000269|PubMed:12297508, ECO:0000269|PubMed:12471034, ECO:0000269|PubMed:12522139, ECO:0000269|PubMed:12679784, ECO:0000269|PubMed:12763021, ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:26280335, ECO:0000305}.;

Recessive Scores

pRec: 0.106

Intolerance Scores

LoFtool: 0.646
RVIS EVS: 0.13
RVIS percentile EVS: 62.74

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.963

Gene Damage Prediction

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