PGA3

Chr 11

pepsinogen A3

NCBI Gene: 643834 ENSG00000229859 UniProt: P0DJD8 OMIM: 169710

This gene encodes pepsinogen A, the inactive precursor of pepsin that is secreted by gastric chief cells and undergoes autocatalytic cleavage in acidic conditions to form the active digestive enzyme. Pepsin functions as an endopeptidase with broad specificity for protein digestion, showing particular preference for bonds involving phenylalanine and leucine. No Mendelian diseases have been definitively associated with mutations in this gene.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein precursor of the digestive enzyme pepsin, a member of the peptidase A1 family of endopeptidases. The encoded precursor is secreted by gastric chief cells and undergoes autocatalytic cleavage in acidic conditions to form the active enzyme, which functions in the digestion of dietary proteins. This gene is found in a cluster of related genes on chromosome 11, each of which encodes one of multiple pepsinogens. Pepsinogen levels in serum may serve as a biomarker for atrophic gastritis and gastric cancer. [provided by RefSeq, Jul 2015]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.25

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.25LOEUF

pLI 0.105

Z-score 1.24

OE 0.40 (0.16–1.25)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.14Z-score

OE missense 0.55 (0.41–0.75)

28 obs / 50.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.40 (0.16–1.25)

0≤0.351.4

Missense OE?0.55 (0.41–0.75)

0≤0.61.4

Synonymous OE?0.70

0≤1.21.6

LoF obs/exp: 2 / 5.0Missense obs/exp: 28 / 50.9Syn Z: 1.15

Background carrier burden — how many people carry a rare variant somewhere in PGA3?

gnomAD v4 · ~730k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 220

47 rare PASS variants

Rare truncating (LoF)

1 in 2,800

14 rare PASS variants

Rare synonymous (reference)

1 in 800

22 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PGA3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 8 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 440	1 in 1,600
South Asian	~43k	1 in 430	≈ 1 in 13,000
Remaining (unassigned)	~30k	1 in 270	≈ 1 in 10,000
European (Finnish)	~27k	1 in 510	none seen
Admixed American	~22k	1 in 270	≈ 1 in 22,000
African / African American	~21k	1 in 390	≈ 1 in 16,000
East Asian	~20k	1 in 1,400	≈ 1 in 19,000
Ashkenazi Jewish	~13k	≈ 1 in 6,500	1 in 2,000

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): 1 of 9 coding exons well covered in gnomAD exomes; exons 3, 4, 5, 6, 7, 9 poorly covered; exons 2, 8 marginal. Genomes: 0 of 9 (exons 1, 2, 3, 4, 5 and 4 more below).? see exons ↓