| Variant (protein or HGVS) | Evidence source (year) | Phenotype/subtype association | Residual α-NAGA activity (if reported) | Mechanistic/structural notes |
|---|---|---|---|---|
| p.E325K; c.973G>A | Wang et al. (1990) | Infantile Schindler disease / type I; infantile neuroaxonal dystrophy in two brothers from a consanguineous family (pqac-00000054) | Affected individuals: **<1% of normal**; parents showed intermediate activity consistent with heterozygosity (pqac-00000054) | Missense substitution in NAGA causing inactive enzyme; patient fibroblasts had **no detectable immunoreactive enzyme**, while transient expression produced immunoreactive but inactive protein, supporting instability/loss of function (pqac-00000054) |
| p.E325K/E325K | Keulemans et al. (1996) | Severe infantile neuroaxonal dystrophy; two affected sibs and an additional consanguineous patient with severe neurologic disease/convulsions (pqac-00000052) | Not numerically reported in this excerpt; severe deficiency implied (pqac-00000052) | Keulemans emphasized a **genotype-phenotype paradox**: identical homozygous genotype associated with severe infantile disease, while other NAGA genotypes could present much more mildly (pqac-00000052) |
| p.E325K | Sakuraba et al. (2004) | Type I Schindler disease; early-onset infantile neuroaxonal dystrophy (pqac-00000040, pqac-00000041) | **0.6-1.7% of control** in homozygotes (pqac-00000040) | Located distant from the active site; inferred to yield an **unstable protein rapidly degraded** rather than directly disrupting catalytic residues (pqac-00000040) |
| p.R329W | Sakuraba et al. (2004) | Kanzaki disease / type II; late-onset angiokeratoma corporis diffusum phenotype (pqac-00000040, pqac-00000041) | **Below 1% of control** in patients homozygous for reported pathogenic alleles (pqac-00000040) | Structural modeling predicted **major destabilization at the domain I-II interface**; associated with lysosomal storage of **Tn-antigen** in fibroblasts (pqac-00000040, pqac-00000061) |
| p.R329Q | Sakuraba et al. (2004) | Kanzaki disease / type II; adult-onset/milder phenotype (pqac-00000040, pqac-00000041) | **Below 1% of control** in patients homozygous for reported pathogenic alleles (pqac-00000040) | Similar to p.R329W, predicted to cause **major conformational destabilization**; part of the paradox in which very low enzyme activity can still accompany milder adult disease (pqac-00000040, pqac-00000041) |
| p.E193* (reported as E193X); c.577G>T | Keulemans et al. (1996); Castro et al. (2019) | Mild/adult end of spectrum in Spanish patients and in a 68-year-old man clinically compatible with Kanzaki disease / type II (pqac-00000052, pqac-00000039, pqac-00000042) | **~0.2% of control** in E193X homozygotes (Sakuraba summary of Spanish patients) (pqac-00000040); Castro reports diminished activity qualitatively (pqac-00000039) | **Null/nonsense mutation** with complete loss of α-NAGA protein; despite this, phenotype may be relatively mild/adult-onset, illustrating marked genotype-phenotype discordance (pqac-00000040, pqac-00000052) |
| p.S160C | Keulemans et al. (1996) | Reported among additional pathogenic mutations in α-NAGA deficiency; specific subtype not detailed in retrieved excerpt (pqac-00000052) | Not reported in retrieved excerpt (pqac-00000052) | One of the "two new mutations" reported in 1996; included as evidence for allelic heterogeneity in NAGA deficiency (pqac-00000052) |
| Biallelic missense variants (8 probands) and 1 homozygous nonsense variant | Groopman et al. / ClinGen LD GCEP (2024) | Spectrum includes Schindler disease types I and III and Kanzaki disease/type II; clinically unaffected relatives with same genotype and enzyme deficiency have been reported (pqac-00000049) | All reported individuals with biallelic variants had **α-NAGA enzyme deficiency**, but exact residual activities varied by report (pqac-00000049) | ClinGen classified the NAGA-disease relationship as **Definitive** (11.85 points, rounded to 12) while noting that the **clinical impact/penetrance remains unclear**, supporting variable expressivity beyond enzyme deficiency alone (pqac-00000049) |


*Table: This table summarizes key reported pathogenic NAGA variants in Schindler/Kanzaki disease, linking each to subtype associations, residual enzyme activity, and mechanistic interpretations. It is useful for quick curation of genotype-phenotype relationships and the notable variability in clinical expression.*