# NM_000169.3(GLA):c.945C>T (p.Asp315=)

https://sugi.bio/variant/gla-p-asp315

## Summary

**GLA p.Asp315= (c.945C>T)** is classified **Conflicting classifications of pathogenicity** in GLA (ClinVar, Conflicting submitters, 19 submitters; last evaluated 2026-09-08). Ultra-rare (popmax 0.033%, nfe); Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs151208856 · 19 submitters · 2 linked conditions · ultra-rare (popmax 0.033%, nfe)

## For patients & families {#patients}

This is a change in the GLA gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 19 submitters, 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.Asp315= |
| Coding change (HGVS c.) | c.945C>T |
| MANE Select transcript | [NM_000169](https://www.ncbi.nlm.nih.gov/nuccore/NM_000169) |
| dbSNP | [rs151208856](https://www.ncbi.nlm.nih.gov/snp/rs151208856/) |
| Variant type | single nucleotide variant |
| Location | chrX:101398424-101398424 (GRCh38) |
| ClinVar | [VCV42465](https://www.ncbi.nlm.nih.gov/clinvar/variation/42465/) |

**All HGVS expressions:** `LRG_672:g.14540C>T`, `LRG_672t1:c.945C>T`, `NC_000023.10:g.100653412G>A`, `NC_000023.11:g.101398424G>A`, `NG_007119.1:g.14540C>T`, `NM_000169.2(GLA):c.945C>T`, `NM_000169.3:c.945C>T`, `NM_001199973.2:c.300+2967G>A`, `NM_001199974.2:c.177+6602G>A`, `NM_001406747.1:c.1068C>T`, `NM_001406748.1:c.945C>T`, `NR_164783.1:n.1024C>T`, `NR_176252.1:n.875C>T`, `NR_176253.1:n.1082C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 3.939, GERP -0.164, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 6.93**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.86 donor gain), 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 (gnomAD v4.1): grpmax **0.033%** (nfe) · FAF95 0.0299% · FAF99 0.0287% · 295/893,618 in the highest group · 311/1,207,797 alleles overall — ultra-rare (popmax 0.033%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.033% | 3,029 |
| Remaining individuals (not grpmax-eligible) | 0.0168% | 5,939 |
| Admixed American | 0.011% | 9,131 |
| African / African-American | 0.00351% | 28,506 |
| South Asian | 0.00176% | 56,730 |

*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 **315** lies in a UniProt-annotated variant site (in fabryd; uncertain significance; decreased enzyme activity); an α-helix.

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-09-08.

**Submitter consensus:** conflicting (15 Likely benign, 3 Benign, 1 Uncertain significance).

**Submission history:** 14 submissions (2012–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2012-12-11 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2017-11-16 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Likely benign | no assertion criteria provided | clinical testing |  |
| Genome-Nilou Lab | Likely benign | criteria provided, single submitter | clinical testing | 2021-07-15 |
| Natera, Inc. | Likely benign | no assertion criteria provided | clinical testing | 2021-07-25 |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-09 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-07-31 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Likely benign | no assertion criteria provided | clinical testing |  |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2013-06-17 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Likely benign | criteria provided, single submitter | curation | 2020-01-22 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2021-01-19 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2020-09-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-13 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-08-01 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2018-10-30 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Genomenon, Inc, Genomenon, Inc | Likely benign | criteria provided, single submitter | curation | 2026-09-08 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not specified, Fabry disease, not provided, GLA-related disorder, GLA-related condition, AllHighlyPenetrant, none provided, CERAMIDE TRIHEXOSIDASE DEFICIENCY, ALPHA-GALACTOSIDASE A DEFICIENCY.

## Same-residue context {#hotspot}

Residue **315** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [GLA p.Asp315_Val316insTer](/variant/gla-p-asp315-val316inster). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related GLA variant pages (same residue, condition, or type): [GLA p.Asp315Asn](/variant/gla-p-asp315asn), [GLA p.Asp315_Val316insTer](/variant/gla-p-asp315-val316inster), [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 42465). 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.*