# NM_000169.3(GLA):c.991C>T (p.Leu331Phe)

https://sugi.bio/variant/gla-p-leu331phe

## Summary

**GLA p.Leu331Phe (c.991C>T)** is classified **Conflicting classifications of pathogenicity** in GLA (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-11-10). AlphaMissense: likely benign (0.0981); Very rare (popmax 0.00113%, nfe); Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs730880437 · 7 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00113%, 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 7 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.Leu331Phe |
| Coding change (HGVS c.) | c.991C>T |
| MANE Select transcript | [NM_000169](https://www.ncbi.nlm.nih.gov/nuccore/NM_000169) |
| dbSNP | [rs730880437](https://www.ncbi.nlm.nih.gov/snp/rs730880437/) |
| Variant type | single nucleotide variant |
| Location | chrX:101398378-101398378 (GRCh38) |
| ClinVar | [VCV180828](https://www.ncbi.nlm.nih.gov/clinvar/variation/180828/) |

**All HGVS expressions:** `LRG_672:g.14586C>T`, `LRG_672t1:c.991C>T`, `NC_000023.10:g.100653366G>A`, `NC_000023.11:g.101398378G>A`, `NG_007119.1:g.14586C>T`, `NM_000169.2(GLA):c.991C>T`, `NM_000169.3:c.991C>T`, `NM_001199973.2:c.300+2921G>A`, `NM_001199974.2:c.177+6556G>A`, `NM_001406747.1:c.1114C>T`, `NM_001406748.1:c.991C>T`, `NR_164783.1:n.1070C>T`, `NR_176252.1:n.921C>T`, `NR_176253.1:n.1128C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0981)
- REVEL 0.375 (indeterminate)
- SaProt LLR -8.098 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 3.932, GERP 2.5, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.1**. 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 (G>C, Δ0.46 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 **0.00113%** (nfe) · FAF95 0.000574% · FAF99 0.000418% · 10/881,641 in the highest group · 10/1,194,896 alleles overall — very rare (popmax 0.00113%, nfe).

*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 **331** lies in 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-10.

**Submitter consensus:** conflicting (6 Uncertain significance, 1 Likely benign).

**Submission history:** 7 submissions (2014–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CSER _CC_NCGL, University of Washington | Uncertain significance | criteria provided, single submitter | research | 2016-10-01 |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Uncertain significance | criteria provided, single submitter | curation | 2020-01-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-21 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2014-03-28 |
| Genome-Nilou Lab | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-15 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-09-07 |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-10 |

## 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, AllHighlyPenetrant, Fabry's disease, HEREDITARY DYSTOPIC LIPIDOSIS, Angiokeratoma corporis diffusum, ALPHA-GALACTOSIDASE A DEFICIENCY, ANDERSON-FABRY DISEASE, CERAMIDE TRIHEXOSIDASE DEFICIENCY.

## Similar variants {#similar}

Related GLA variant pages (same residue, condition, or type): [GLA p.Leu331Ile](/variant/gla-p-leu331ile), [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), [GLA c.195-1G>C](/variant/gla-c-195-minus-1g-c).

### 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 180828). 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.*