NAALAD2

Chr 11

N-acetylated alpha-linked acidic dipeptidase 2

Also known as: GCP3, GCPIII, GPCIII

NCBI Gene: 10003 ENSG00000077616 UniProt: Q9Y3Q0 OMIM: 611636

The NAALAD2 protein functions as an N-acetylated-alpha-linked-acidic dipeptidase that inactivates the peptide neurotransmitter N-acetylaspartylglutamate and exhibits dipeptidyl-peptidase IV activity. Mutations in NAALAD2 cause autosomal recessive spastic paraplegia with intellectual disability and thin corpus callosum. This gene is not highly constrained against loss-of-function variants, with prominent expression in brain, ovary, and testis.

OMIM ResearchSummary from RefSeq, UniProt

This gene is a member of the N-acetylated alpha-linked acidic dipeptidase (NAALADase) gene family. The representative member of this family is the gene encoding human prostate-specific membrane antigen (PSM), which is a marker of prostatic carcinomas and is the first to be shown to possess NAALADase activity. NAALADase cleaves N-acetyl-L-aspartate-L-glutamate (NAAG), which is a neuropeptide expressed both in the central nervous systems and in the periphery and is thought to function as a neurotransmitter. The product of this gene is a type II integral membrane protein. Transient transfection of this gene confers both NAALADase and dipetidyl peptidase IV activities to mammalian cells. This gene is highly expressed in ovary and testis as well as within discrete brain areas. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.09

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.09LOEUF

pLI 0.000

Z-score 1.07

OE 0.82 (0.63–1.09)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.47Z-score

OE missense 0.93 (0.85–1.02)

359 obs / 385.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.82 (0.63–1.09)

0≤0.351.4

Missense OE?0.93 (0.85–1.02)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 35 / 42.6Missense obs/exp: 359 / 385.2Syn Z: 0.33

Background carrier burden — how many people carry a rare variant somewhere in NAALAD2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 74

1,013 rare PASS variants

Rare truncating (LoF)

1 in 580

227 rare PASS variants

Rare synonymous (reference)

1 in 130

276 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NAALAD2. 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 100	1 in 740
South Asian	~43k	1 in 57	1 in 380
Remaining (unassigned)	~30k	1 in 57	1 in 450
European (Finnish)	~27k	1 in 240	1 in 670
Admixed American	~22k	1 in 61	1 in 320
African / African American	~21k	1 in 62	1 in 210
East Asian	~20k	1 in 69	1 in 210
Ashkenazi Jewish	~13k	1 in 330	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 71	1 in 360

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): 13 of 19 coding exons well covered in gnomAD exomes; exons 4, 5, 7, 9, 13, 17 marginal. Genomes: all 19.? see exons ↓