# NM_000169.3(GLA):c.588A>C (p.Arg196Ser)

https://sugi.bio/variant/gla-p-arg196ser

## Summary

**GLA p.Arg196Ser (c.588A>C)** is classified **Uncertain significance** in GLA (ClinVar, Single submitter, 2 submitters; last evaluated 2026-09-08). AlphaMissense: likely pathogenic (0.5785); Absent from gnomAD v4.1; Associated with Fabry disease.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs869312147 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the GLA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Fabry disease.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | X-linked dominant, X-linked recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-9 / 1 000 000 (Worldwide) |
| Clinical trials | 228 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | GLA is a diagnostic-grade gene on 27 Genomics England panels |

**Commonly reported features of Fabry disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Renal insufficiency — Very frequent (99-80%)
- Nephrotic syndrome — Very frequent (99-80%)
- Hearing impairment — Very frequent (99-80%)
- Conjunctival telangiectasia — Very frequent (99-80%)
- Hematuria — Very frequent (99-80%)
- Hyperkeratosis — Very frequent (99-80%)
- Hypohidrosis — Very frequent (99-80%)
- Angiokeratoma — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006400/index) · [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.Arg196Ser |
| Coding change (HGVS c.) | c.588A>C |
| MANE Select transcript | [NM_000169](https://www.ncbi.nlm.nih.gov/nuccore/NM_000169) |
| dbSNP | [rs869312147](https://www.ncbi.nlm.nih.gov/snp/rs869312147/) |
| Variant type | single nucleotide variant |
| Location | chrX:101400717-101400717 (GRCh38) |
| ClinVar | [VCV217389](https://www.ncbi.nlm.nih.gov/clinvar/variation/217389/) |

**All HGVS expressions:** `LRG_672:g.12247A>C`, `LRG_672t1:c.588A>C`, `NC_000023.10:g.100655705T>G`, `NC_000023.11:g.101400717T>G`, `NG_007119.1:g.12247A>C`, `NM_000169.3:c.588A>C`, `NM_001199973.2:c.300+5260T>G`, `NM_001199974.2:c.177+8895T>G`, `NM_001406747.1:c.711A>C`, `NM_001406748.1:c.588A>C`, `NR_164783.1:n.610A>C`, `NR_176253.1:n.725A>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.5785)
- REVEL 0.905 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.135 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 6.143, GERP 2.8, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.3**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.66** across the covering region of the MANE Select transcript (101,397,812–101,403,879), spanning 6,067 bp. Chi-square p 6.6e-08. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.31 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **196** lies in a UniProt-annotated variant site (in fabryd; uncertain significance; decreased enzyme activity).

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-09-08.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 drug response).

**Submission history:** 3 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Albrecht-Kossel-Institute, Medical University Rostock | Uncertain significance | no assertion criteria provided | research | 2014-01-01 |
| Albrecht-Kossel-Institute, Medical University Rostock | drug response | no assertion criteria provided | research | 2014-01-01 |
| Genomenon, Inc, Genomenon, Inc | Uncertain significance | criteria provided, single submitter | curation | 2026-09-08 |

## Associated conditions {#conditions}

[Fabry disease](https://sugi.bio/atlas/disease/fabry-disease/).

**Reported phenotype names (ClinVar):** Fabry disease, Migalastat response, ALPHA-GALACTOSIDASE A DEFICIENCY, ANDERSON-FABRY DISEASE, CERAMIDE TRIHEXOSIDASE DEFICIENCY, Fabry's disease, Angiokeratoma corporis diffusum, Ceramide trihexosidosis, GLA DEFICIENCY, HEREDITARY DYSTOPIC LIPIDOSIS.

## Same-residue context {#hotspot}

Residue **196** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [GLA p.Arg196fs](/variant/gla-p-arg196fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related GLA variant pages (same residue, condition, or type): [GLA p.Arg196Thr](/variant/gla-p-arg196thr), [GLA p.Arg196fs](/variant/gla-p-arg196fs), [GLA c.1000-10G>A](/variant/gla-c-1000-minus-10g-a), [GLA c.1000-1G>A](/variant/gla-c-1000-minus-1g-a), [GLA c.1000-1G>C](/variant/gla-c-1000-minus-1g-c), [GLA c.1023A>C](/variant/gla-c-1023a-c), [GLA c.194+1G>A](/variant/gla-c-194-plus-1g-a), [GLA c.194+1G>T](/variant/gla-c-194-plus-1g-t).

### 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 217389). 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.*