APH1B

Chr 15

aph-1B gamma-secretase subunit

Also known as: APH-1B, PRO1328, PSFL, TAAV688, aph-1beta

NCBI Gene: 83464 ENSG00000138613 UniProt: Q8WW43 OMIM: 607630

This gene encodes a multi-pass transmembrane protein that is a functional component of the gamma-secretase complex, which also contains presenilin and nicastrin. This protein represents a stabilizing cofactor for the presenilin holoprotein in the complex. The gamma-secretase complex catalyzes the cleavage of integral proteins such as notch receptors and beta-amyloid precursor protein. [provided by RefSeq, Sep 2011]

OMIM Research

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.74

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.74LOEUF

pLI 0.000

Z-score -0.53

OE 1.16 (0.77–1.74)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.18Z-score

OE missense 1.04 (0.91–1.20)

147 obs / 141.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.16 (0.77–1.74)

0≤0.351.4

Missense OE?1.04 (0.91–1.20)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 15 / 12.9Missense obs/exp: 147 / 141.0Syn Z: -0.39

Background carrier burden — how many people carry a rare variant somewhere in APH1B?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

370 rare PASS variants

Rare truncating (LoF)

1 in 1,000

76 rare PASS variants

Rare synonymous (reference)

1 in 810

120 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for APH1B. 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 180	1 in 990
South Asian	~43k	1 in 110	1 in 2,200
Remaining (unassigned)	~30k	1 in 160	1 in 1,900
European (Finnish)	~27k	1 in 740	≈ 1 in 27,000
Admixed American	~22k	1 in 140	1 in 1,600
African / African American	~21k	1 in 110	1 in 620
East Asian	~20k	1 in 84	1 in 1,400
Ashkenazi Jewish	~13k	1 in 1,000	1 in 2,600
Middle Eastern	~2,884	1 in 93	≈ 1 in 2,900

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): 6 of 6 coding exons well covered in gnomAD exomes. Genomes: 5 of 6 (exon 1 below).? see exons ↓