# NM_000169.3(GLA):c.661C>T (p.Gln221Ter)

https://sugi.bio/variant/gla-p-gln221ter

## Summary

**GLA p.Gln221Ter (c.661C>T)** is classified **Pathogenic** in GLA (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-09-08). Absent from gnomAD v4.1; Associated with Fabry disease.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs797044747 · 5 submitters · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the GLA gene that is considered disease-causing, submitted by 5 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 |

**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.Gln221Ter |
| Coding change (HGVS c.) | c.661C>T |
| dbSNP | [rs797044747](https://www.ncbi.nlm.nih.gov/snp/rs797044747/) |
| Variant type | single nucleotide variant |
| Location | chrX:101398925-101398925 (GRCh38) |
| ClinVar | [VCV197638](https://www.ncbi.nlm.nih.gov/clinvar/variation/197638/) |

**All HGVS expressions:** `LRG_672:g.14039C>T`, `LRG_672t1:c.661C>T`, `NC_000023.10:g.100653913G>A`, `NC_000023.11:g.101398925G>A`, `NG_007119.1:g.14039C>T`, `NM_000169.3:c.661C>T`, `NM_001199973.2:c.300+3468G>A`, `NM_001199974.2:c.177+7103G>A`, `NM_001406747.1:c.784C>T`, `NM_001406748.1:c.661C>T`, `NR_164783.1:n.740C>T`, `NR_176252.1:n.591C>T`, `NR_176253.1:n.798C>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 0.214, GERP 0.133, phastCons 0.003 — weakly conserved position
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- CADD: **PHRED 33.0**. 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.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Pangolin: Δ**0.44** (loss), gain 0.00 / loss 0.44. 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.*

## Clinical significance {#significance}

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

**Submitter consensus:** unanimous (5/5 Pathogenic).

**Submission history:** 5 submissions (2014–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome-Nilou Lab | Pathogenic | criteria provided, single submitter | clinical testing | 2021-07-15 |
| Genomenon, Inc, Genomenon, Inc | Pathogenic | criteria provided, single submitter | curation | 2026-09-08 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2019-07-03 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2014-07-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2019-12-15 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Fabry disease, not provided, none provided, Ceramide trihexosidosis, Angiokeratoma corporis diffusum, ALPHA-GALACTOSIDASE A DEFICIENCY, ANDERSON-FABRY DISEASE, Fabry's disease, CERAMIDE TRIHEXOSIDASE DEFICIENCY, GLA DEFICIENCY.

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 197638). 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.*