# NM_000169.3(GLA):c.194G>T (p.Ser65Ile)

https://sugi.bio/variant/gla-p-ser65ile

## Summary

**GLA p.Ser65Ile (c.194G>T)** is classified **Pathogenic/Likely pathogenic** in GLA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-09-08). AlphaMissense: likely pathogenic (0.7343); Absent from gnomAD v4.1; Associated with GLA-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · 3 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the GLA gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to GLA-related disorder.

*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.Ser65Ile |
| Coding change (HGVS c.) | c.194G>T |
| MANE Select transcript | [NM_000169](https://www.ncbi.nlm.nih.gov/nuccore/NM_000169) |
| Variant type | single nucleotide variant |
| Location | chrX:101407710-101407710 (GRCh38) |
| ClinVar | [VCV4087297](https://www.ncbi.nlm.nih.gov/clinvar/variation/4087297/) |

**All HGVS expressions:** `LRG_672:g.5254G>T`, `LRG_672t1:c.194G>T`, `NC_000023.10:g.100662698C>A`, `NC_000023.11:g.101407710C>A`, `NG_007119.1:g.5254G>T`, `NG_016327.1:g.4508C>A`, `NM_000169.3:c.194G>T`, `NM_001199973.2:c.301-4226C>A`, `NM_001199974.2:c.178-4226C>A`, `NM_001406747.1:c.194G>T`, `NM_001406748.1:c.194G>T`, `NM_001406749.1:c.194G>T`, `NR_164783.1:n.216G>T`, `NR_176252.1:n.216G>T`, `NR_176253.1:n.216G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7343) — concordant with the pathogenic call
- REVEL 0.816 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.398 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **donor gain** (Δ 0.91) — consistent with the pathogenic call
- Conservation: phyloP 7.563, GERP 3.29, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 38.0**. 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 0.25** across the covering region of the MANE Select transcript (101,403,880–101,407,779), spanning 3,899 bp — the region is depleted of missense variation. Chi-square p 4.8e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.54**, acceptor gain **0.00**, donor gain **0.91**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.54**, acceptor gain **0.00**, donor gain **0.91**.
- Pangolin: Δ**0.74** (loss), gain 0.48 / loss 0.74. SpliceAI calls gain. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is 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 **65** lies in a β-strand; a UniProt-annotated variant site (in fabryd; does not affect enzyme function).

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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-09-08.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2024–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-07-15 |
| Genomenon, Inc, Genomenon, Inc | Pathogenic | criteria provided, single submitter | curation | 2026-09-08 |

## Associated conditions {#conditions}

[GLA-related disorder](https://sugi.bio/atlas/disease/gla-related-disorder/), [Fabry disease](https://sugi.bio/atlas/disease/fabry-disease/).

**Reported phenotype names (ClinVar):** GLA-related disorder, Fabry disease, Nonpapillary renal cell carcinoma, Thyroid cancer, nonmedullary, 1, GLA-related condition, ALPHA-GALACTOSIDASE A DEFICIENCY, ANDERSON-FABRY DISEASE, CERAMIDE TRIHEXOSIDASE DEFICIENCY, GLA DEFICIENCY, HEREDITARY DYSTOPIC LIPIDOSIS.

## Same-residue context {#hotspot}

Residue **65** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [GLA p.Ser65Thr](/variant/gla-p-ser65thr). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related GLA variant pages (same residue, condition, or type): [GLA p.Ser65=](/variant/gla-p-ser65), [GLA p.Ser65Thr](/variant/gla-p-ser65thr), [GLA p.Ser65Asn](/variant/gla-p-ser65asn), [GLA p.Ser65Ala](/variant/gla-p-ser65ala), [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).

### 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 4087297). 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.*