| Disease/Condition | Key Findings | Evidence Type | Year of Publication | Citations |
|---|---|---|---|---|
| Prostate cancer / castration-resistant prostate cancer (CRPC) | In orthograft models of CRPC, NAALADL2 protein was increased across all three CRPC models, alongside elevated tumoral NAA and NAAG. A gene set including **FOLH1, NAALADL2, ACSS1, ACY1, GOT1/2, ASNS** was associated with worse overall survival in public prostate cancer cohorts: altered cases **n=12**, median OS **70 months** vs **131 months** in unaltered cases (**n=140**), BH-adjusted log-rank **P=5.99×10⁻⁴**; altered cases also had more ADT exposure, metastatic disease, and higher Gleason grade. The study interprets NAALADL2 as part of a pathway converting NAAG to NAA that may support tumor metabolism in CRPC. Separately, NAALADL2-related circulating biomarkers were observed in mCRPC: **NAALADL2-AS2** levels >2-fold above healthy controls, and low NAALADL2-AS2 was associated with shorter time to progression (**11.5 months vs not reached**, log-rank **P=0.01**). Regulatory-SNP analysis also identified NAALADL2 among prostate-cancer recurrence-associated target genes. (pqac-00000005, pqac-00000003) | Proteomics/transcriptomics/metabolomics; survival association; liquid-biomarker study; regulatory SNP/gene-expression association | 2022, 2020, 2016 | (pqac-00000005, pqac-00000003) |
| Neurodevelopmental disorders (NDDs) | Optical genome mapping of 47 unsolved NDD families identified an **897 kb inversion** at **3q26.31** disrupting **NAALADL2** by inversion of several exons in one family. The authors note prior reports of complex rearrangements in NAALADL2 in two NDD cases, suggest the locus is prone to rearrangement, and note that loss-of-function structural variants are rare in gnomAD v4.0.0. The study frames NAALADL2 as a candidate NDD gene because it belongs to the glutamate carboxypeptidase family and is involved in glutamate metabolism. Diagnostic yield of likely pathogenic/pathogenic SVs in the OGM study was **5/47 families (10.6%)**, though the NAALADL2 inversion remained a VUS/candidate finding. (pqac-00000002, pqac-00000010) | Structural-variant discovery / candidate-gene study using optical genome mapping | 2024 | (pqac-00000002, pqac-00000010) |
| Kawasaki disease | A GWAS with replication/fine-mapping identified **NAALADL2 rs17531088** among the strongest replicated loci for Kawasaki disease susceptibility, with combined **P=1.13×10⁻⁶**. The overall study included **893 KD cases** plus controls/families, and NAALADL2 was one of four loci where neighboring markers were more significant than the original signal after fine-mapping. Blood transcript levels for fine-mapped genes showed a trend toward reduced expression during acute disease before treatment. (pqac-00000000) | GWAS with replication and fine-mapping | 2009 | (pqac-00000000) |
| Alzheimer’s disease | A 2024 multimodal feature-fusion/deep-learning study using ADNI data reported **NAALADL2** among **six novel genes** significantly associated with Alzheimer’s disease. The model achieved classification performance of **93.44% ACC / 96.67% AUC** for AD vs healthy control, **89.06% / 92%** for AD vs MCI, and **84% / 81.84%** for HC vs MCI. The paper presents NAALADL2 as an association discovery rather than a mechanistic validation. (pqac-00000002) | Computational genomics / multimodal association study | 2024 | (pqac-00000002) |
| Adipocyte hypertrophy / cardiometabolic disease | A 2025 preprint GWAS of adipocyte size identified **rs73184721** in **NAALADL2** as one of **four genome-wide significant loci** for adipocyte hypertrophy in the largest study of its kind, with **N=2,066** subcutaneous and **N=1,878** visceral adipose samples. The authors note the variant is intronic and that NAALADL2 function remains largely unknown; the association was reported to align with cardiometabolic trait relationships. (pqac-00000002) | GWAS of image-derived adipocyte morphology | 2025 | (pqac-00000002) |
| Liver cirrhosis / hepatic fibrosis | Single-cell transcriptomic analysis of human cirrhotic liver identified **NAALADL2** as highly expressed in **myofibroblasts (MFBs)** in human liver, placing it among marker genes associated with mesenchymal-cell differentiation and fibrotic remodeling. The report is expression-based and does not establish direct mechanism for NAALADL2. (pqac-00000002) | Single-cell RNA-seq / cell-state marker study | 2024 | (pqac-00000002) |
| Breast cancer (young women) | Recurrent copy-number analysis in young women with breast cancer identified validated recurrent **copy-number gain regions** encompassing **NAALADL2** on chromosome 3. The study’s snippet also notes prior evidence that NAALADL2 is basal-localized and that overexpression has been associated with poorer survival, although the present paper is principally a CNA analysis rather than a direct NAALADL2 functional study. (pqac-00000006) | Copy-number alteration study | 2018 | (pqac-00000006) |
| Metastatic castration-resistant prostate cancer biomarker context | In whole-blood liquid-biopsy profiling of **40 mCRPC patients**, **NAALADL2-AS2** was one of the few circulating RNAs >2-fold elevated vs healthy controls. Higher NAALADL2-AS2 levels were associated with longer time to progression, contrasting with miR-375 and miR-3687, which predicted shorter progression-free intervals. This supports clinical relevance of the NAALADL2 locus in prostate cancer, though it concerns the antisense lncRNA rather than the protein-coding gene product directly. (pqac-00000003) | Prospective observational biomarker study | 2020 | (pqac-00000003) |


*Table: This table summarizes reported disease links and clinical relevance of NAALADL2 across cancer, neurodevelopmental, cardiovascular, metabolic, and liver-related contexts. It prioritizes recent 2023-2024 findings where available and includes quantitative details such as SNPs, inversion sizes, cohort sizes, survival data, and p-values.*