# NM_000169.3(GLA):c.1210dup (p.Arg404fs)

https://sugi.bio/variant/gla-p-arg404fs

## Summary

**GLA p.Arg404fs (c.1210dup)** is classified **Pathogenic** in GLA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-31). No gnomAD frequency available for this variant; Associated with Cardiovascular phenotype.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2520849107 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the GLA gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Cardiovascular phenotype.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GLA](https://sugi.bio/atlas/gene/GLA/) |
| Protein change (HGVS p.) | p.Arg404fs |
| Coding change (HGVS c.) | c.1210dup |
| MANE Select transcript | [NM_000169](https://www.ncbi.nlm.nih.gov/nuccore/NM_000169) |
| dbSNP | [rs2520849107](https://www.ncbi.nlm.nih.gov/snp/rs2520849107/) |
| Variant type | Duplication |
| Location | chrX:101397888-101397889 (GRCh38) |
| ClinVar | [VCV1750330](https://www.ncbi.nlm.nih.gov/clinvar/variation/1750330/) |

**All HGVS expressions:** `LRG_672:g.15075dup`, `LRG_672t1:c.1209dup`, `NC_000023.10:g.100652878dup`, `NC_000023.11:g.101397890dup`, `NG_007119.1:g.15075dup`, `NM_000169.2:c.1210dupA`, `NM_000169.3:c.1210dup`, `NM_001199973.2:c.300+2433dup`, `NM_001199974.2:c.177+6068dup`, `NM_001406747.1:c.1333dup`, `NR_164783.1:n.1289dup`, `NR_176252.1:n.1140dup`, `NR_176253.1:n.1347dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 3.479, GERP 0.774, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (7 of 7)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**GLA** population constraint: ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Fabry disease** — Definitive (XL)

## Protein context {#protein}

Residue **404** lies in a UniProt-annotated variant site (in fabryd; loss of enzyme activity); a β-strand.

AlphaFold model confidence (whole protein): pLDDT 94.45, 90% of residues very-high.

**31 experimental structure(s)** (PDB): [1R46](https://www.rcsb.org/structure/1R46), [1R47](https://www.rcsb.org/structure/1R47), [3GXN](https://www.rcsb.org/structure/3GXN), [3GXP](https://www.rcsb.org/structure/3GXP), [3GXT](https://www.rcsb.org/structure/3GXT), [3HG2](https://www.rcsb.org/structure/3HG2).

## What this gene does {#gene-function}

*Describes the biological roles of GLA (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** GLA's established molecular role includes catalytic activity.


### Pathways affected {#pathways}

GLA participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glycosphingolipid catabolism](https://reactome.org/content/detail/R-HSA-9840310) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** catalytic activity, alpha-galactosidase activity, signaling receptor binding, protein homodimerization activity.

**Biological process:** oligosaccharide metabolic process, glycosphingolipid catabolic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-31.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-08-31 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype.

## Same-residue context {#hotspot}

Residue **404** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [GLA p.Arg404del](/variant/gla-p-arg404del). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related GLA variant pages (same residue, condition, or type): [GLA p.Arg404del](/variant/gla-p-arg404del), [GLA p.Gln99fs](/variant/gla-p-gln99fs), [GLA p.Arg404Lys](/variant/gla-p-arg404lys), [GLA c.802-2A>T](/variant/gla-c-802-minus-2a-t), [GLA p.Ala143Pro](/variant/gla-p-ala143pro), [GLA p.Arg112His](/variant/gla-p-arg112his), [GLA p.Arg112Leu](/variant/gla-p-arg112leu), [GLA p.Arg301Gln](/variant/gla-p-arg301gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1750330). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*