APH1A

Chr 1

aph-1A gamma-secretase subunit

Also known as: 6530402N02Rik, APH-1, APH-1A, CGI-78

NCBI Gene: 51107 ENSG00000117362 UniProt: Q96BI3 OMIM: 607629

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]

OMIM Research

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.45

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.45LOEUF

pLI 0.795

Z-score 2.97

OE 0.14 (0.06–0.45)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.03Z-score

OE missense 0.54 (0.46–0.65)

86 obs / 157.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.14 (0.06–0.45)

0≤0.351.4

Missense OE?0.54 (0.46–0.65)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 2 / 14.0Missense obs/exp: 86 / 157.9Syn Z: 0.51

Background carrier burden — how many people carry a rare variant somewhere in APH1A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 340

266 rare PASS variants

Rare truncating (LoF)

1 in 10,000

32 rare PASS variants

Rare synonymous (reference)

1 in 950

150 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for APH1A. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 670	1 in 10,000
South Asian	~43k	1 in 430	≈ 1 in 11,000
Remaining (unassigned)	~30k	1 in 830	none seen
European (Finnish)	~27k	1 in 2,100	≈ 1 in 6,700
Admixed American	~22k	1 in 450	1 in 3,700
African / African American	~21k	1 in 490	none seen
East Asian	~20k	1 in 190	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 1,600	≈ 1 in 11,000
Middle Eastern	~2,884	1 in 360	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 7 coding exons well covered in gnomAD exomes and genomes.? see exons ↓