NAALADL1

Chr 11

N-acetylated alpha-linked acidic dipeptidase like 1

Also known as: HILAP, I100, NAALADASEL

NCBI Gene: 10004 ENSG00000168060 UniProt: Q9UQQ1 OMIM: 602640

The protein is an aminopeptidase that cleaves peptide bonds with broad substrate specificity and is predicted to localize to the apical plasma membrane. Biallelic mutations in this gene cause autosomal recessive intellectual disability with hypotonia and absent language. The gene shows moderate constraint against loss-of-function variants (LOEUF 1.204), suggesting some tolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

Enables aminopeptidase activity; metal ion binding activity; and protein homodimerization activity. Involved in peptide catabolic process. Predicted to be located in apical plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.20

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.20LOEUF

pLI 0.000

Z-score 0.54

OE 0.90 (0.69–1.20)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.17Z-score

OE missense 0.98 (0.90–1.06)

447 obs / 457.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.90 (0.69–1.20)

0≤0.351.4

Missense OE?0.98 (0.90–1.06)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 34 / 37.6Missense obs/exp: 447 / 457.2Syn Z: 1.34

Background carrier burden — how many people carry a rare variant somewhere in NAALADL1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 40

1,078 rare PASS variants

Rare truncating (LoF)

1 in 520

214 rare PASS variants

Rare synonymous (reference)

1 in 88

411 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NAALADL1. 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 55	1 in 730
South Asian	~43k	1 in 49	1 in 410
Remaining (unassigned)	~30k	1 in 35	1 in 240
European (Finnish)	~27k	1 in 120	1 in 920
Admixed American	~22k	1 in 49	1 in 620
African / African American	~21k	1 in 38	1 in 180
East Asian	~20k	1 in 60	1 in 350
Ashkenazi Jewish	~13k	1 in 320	1 in 1,100
Middle Eastern	~2,884	1 in 43	1 in 580

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 18 coding exons well covered in gnomAD exomes and genomes.? see exons ↓