APH1A

Chr 1

aph-1 homolog A, gamma-secretase subunit

ENSG00000117362UniProt: Q96BI3OMIM: 607629

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:12679784, PubMed:12763021, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). Required for normal gamma-secretase assembly (PubMed:12471034, PubMed:12522139, 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)

OMIMResearchGenerating 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.
0
Active trials
2
Pubs (1 yr)
—
P/LP submissions
—
P/LP missense
0.45
LOEUF
Multiple*
Mechanism· predicted
Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

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

ClinVar

No ClinVar data available.

Protein Context — Lollipop Plot

APH1A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients