GLA

Chr XX-linked

galactosidase alpha

Also known as: GALA

NCBI Gene: 2717 ENSG00000102393 UniProt: Q9UHE5 OMIM: 300644

Alpha-galactosidase A is a lysosomal enzyme that hydrolyzes terminal alpha-galactosyl moieties from glycolipids and glycoproteins, predominantly ceramide trihexoside. Mutations cause Fabry disease, a lysosomal storage disorder that can present as a classic multisystem form or a cardiac variant form. This gene follows X-linked inheritance and is highly constrained against loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a homodimeric glycoprotein that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. This enzyme predominantly hydrolyzes ceramide trihexoside, and it can catalyze the hydrolysis of melibiose into galactose and glucose. A variety of mutations in this gene affect the synthesis, processing, and stability of this enzyme, which causes Fabry disease, a rare lysosomal storage disorder that results from a failure to catabolize alpha-D-galactosyl glycolipid moieties. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Fabry diseaseMIM #301500

X-linked

Fabry disease, cardiac variantMIM #301500

X-linked

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Fabry disease · XL · ClinGen 2019

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

642

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.18

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — GLA

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

LoF Constraint?

0.18LOEUF

pLI 0.997

Z-score 3.80

OE 0.00 (0.00–0.18)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.88Z-score

OE missense 0.58 (0.49–0.69)

93 obs / 159.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.18)

0≤0.351.4

Missense OE?0.58 (0.49–0.69)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 0 / 16.9Missense obs/exp: 93 / 159.7Syn Z: 0.56

Background carrier burden — how many people carry a rare variant somewhere in GLA?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 150

263 rare PASS variants

Rare truncating (LoF)

1 in 13,000

16 rare PASS variants

Rare synonymous (reference)

1 in 380

107 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GLA. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 150	1 in 8,600
South Asian	~36k	1 in 270	≈ 1 in 36,000
Remaining (unassigned)	~31k	1 in 180	≈ 1 in 23,000
European (Finnish)	~27k	1 in 450	none seen
Admixed American	~23k	1 in 190	none seen
African / African American	~21k	1 in 140	1 in 2,700
East Asian	~20k	1 in 260	none seen
Ashkenazi Jewish	~13k	1 in 700	≈ 1 in 13,000
Middle Eastern	~2,758	1 in 390	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 7 coding exons well covered in gnomAD exomes and genomes.? see exons ↓