AGBL1

Chr 15

AGBL carboxypeptidase 1

Also known as: CCP4, FECD8

NCBI Gene: 123624 ENSG00000273540 UniProt: Q96MI9

AGBL1 encodes a metallocarboxypeptidase that removes polyglutamate side chains from tubulin and other proteins through deglutamylation. Mutations cause autosomal dominant Fuchs endothelial corneal dystrophy with late-onset presentation. The gene shows very low constraint to loss-of-function variation (pLI near zero), suggesting the disease mechanism may not involve simple protein loss.

ResearchSummary from RefSeq, OMIM, UniProt

Polyglutamylation is a reversible posttranslational modification catalyzed by polyglutamylases that results in the addition of glutamate side chains on the modified protein. This gene encodes a glutamate decarboxylase that catalyzes the deglutamylation of polyglutamylated proteins. Mutations in this gene result in dominant late-onset Fuchs corneal dystrophy. [provided by RefSeq, Nov 2013]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtCorneal dystrophy, Fuchs endothelial, 8

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.14

LOEUF

—

Mechanism

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.14LOEUF

pLI 0.000

Z-score 0.68

OE 0.90 (0.71–1.14)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-2.23Z-score

OE missense 1.26 (1.19–1.34)

723 obs / 572.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.90 (0.71–1.14)

0≤0.351.4

Missense OE?1.26 (1.19–1.34)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 49 / 54.4Missense obs/exp: 723 / 572.6Syn Z: -1.84

Background carrier burden — how many people carry a rare variant somewhere in AGBL1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 30

1,822 rare PASS variants

Rare truncating (LoF)

1 in 250

263 rare PASS variants

Rare synonymous (reference)

1 in 59

634 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for AGBL1. 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 41	1 in 340
South Asian	~43k	1 in 27	1 in 220
Remaining (unassigned)	~30k	1 in 23	1 in 220
European (Finnish)	~27k	1 in 100	1 in 720
Admixed American	~22k	1 in 23	1 in 260
African / African American	~21k	1 in 21	1 in 130
East Asian	~20k	1 in 37	1 in 170
Ashkenazi Jewish	~13k	1 in 120	≈ 1 in 3,200
Middle Eastern	~2,884	1 in 25	1 in 450

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): 20 of 23 coding exons well covered in gnomAD exomes; exon 23 poorly covered; exons 1, 10 marginal. Genomes: all 23.? see exons ↓