PGA4

Chr 11

pepsinogen A4

NCBI Gene: 643847 ENSG00000229183 UniProt: P0DJD7 OMIM: 169720

The protein is pepsinogen A, a precursor to the digestive enzyme pepsin that is secreted by gastric chief cells and cleaves dietary proteins with broad specificity, particularly favoring bonds involving phenylalanine and leucine. Currently, no Mendelian diseases have been definitively associated with PGA4 mutations in pediatric patients. The gene shows tolerance to loss-of-function variants, suggesting that complete loss may be compatible with normal development.

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…

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

1.87

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.87LOEUF

pLI 0.305

Z-score 0.45

OE 0.00 (0.00–1.87)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.16Z-score

OE missense 1.22 (0.60–1.89)

5 obs / 4.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.00 (0.00–1.87)

0≤0.351.4

Missense OE?1.22 (0.60–1.89)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 0 / 0.2Missense obs/exp: 5 / 4.1Syn Z: 0.02

Background carrier burden — how many people carry a rare variant somewhere in PGA4?

gnomAD v4 · ~190k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 300

16 rare PASS variants

Rare truncating (LoF)

1 in 4,700

2 rare PASS variants

Rare synonymous (reference)

1 in 1,700

13 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PGA4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 7 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~120k	1 in 440	1 in 2,500
South Asian	~18k	1 in 1,300	none seen
East Asian	~14k	≈ 1 in 14,000	none seen
European (Finnish)	~13k	1 in 1,100	none seen
African / African American	~11k	1 in 2,000	1 in 1,200
Remaining (unassigned)	~10k	1 in 390	none seen
Admixed American	~8,037	1 in 740	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): 0 of 9 coding exons well covered in gnomAD exomes; exons 1, 2, 3, 4, 5 and 4 more poorly covered. Genomes: 0 of 9 (exons 1, 2, 3, 4, 5 and 4 more below).? see exons ↓