AGTPBP1

Chr 9AR

ATP/GTP binding carboxypeptidase 1

Also known as: CCP1, CONDCA, NNA1

NCBI Gene: 23287 ENSG00000135049 UniProt: Q9UPW5 OMIM: 606830

AGTPBP1 encodes a metallocarboxypeptidase that removes polyglutamate side chains from tubulin and other proteins, a process called deglutamylation that regulates microtubule dynamics. Mutations cause autosomal recessive childhood-onset neurodegeneration with cerebellar atrophy. The gene is highly constrained against loss-of-function variants (LOEUF 0.351), indicating that complete loss of function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

NNA1 is a zinc carboxypeptidase that contains nuclear localization signals and an ATP/GTP-binding motif that was initially cloned from regenerating spinal cord neurons of the mouse.[supplied by OMIM, Jul 2002]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Neurodegeneration, childhood-onset, with cerebellar atrophyMIM #618276

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · neurodegeneration, childhood-onset, with cerebellar atrophy · AR · ClinGen 2025

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.35

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.35LOEUF

pLI 0.422

Z-score 5.68

OE 0.22 (0.15–0.35)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.01Z-score

OE missense 0.77 (0.72–0.83)

477 obs / 617.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.22 (0.15–0.35)

0≤0.351.4

Missense OE?0.77 (0.72–0.83)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 14 / 62.4Missense obs/exp: 477 / 617.6Syn Z: 0.53

Background carrier burden — how many people carry a rare variant somewhere in AGTPBP1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 56

1,455 rare PASS variants

Rare truncating (LoF)

1 in 1,100

171 rare PASS variants

Rare synonymous (reference)

1 in 120

583 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for AGTPBP1. 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 69	1 in 1,300
South Asian	~43k	1 in 44	1 in 1,100
Remaining (unassigned)	~30k	1 in 46	1 in 1,100
European (Finnish)	~27k	1 in 130	1 in 3,100
Admixed American	~22k	1 in 54	1 in 730
African / African American	~21k	1 in 47	1 in 910
East Asian	~20k	1 in 57	1 in 2,000
Ashkenazi Jewish	~13k	1 in 160	≈ 1 in 4,300
Middle Eastern	~2,884	1 in 49	1 in 580

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 25 coding exons well covered in gnomAD exomes; exons 2, 5, 9, 15, 18 marginal. Genomes: all 25.? see exons ↓