Is GLA p.Leu166= (c.496C>T) pathogenic?

GLA p.Leu166= (c.496C>T) is classified Likely benign in GLA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-02). Very rare (popmax 0.00217%, amr); Associated with Fabry disease.

What condition is associated with GLA p.Leu166= (c.496C>T)?

GLA p.Leu166= (c.496C>T) is associated with Fabry disease (ClinVar).

How common is GLA p.Leu166= (c.496C>T) in the general population?

GLA p.Leu166= (c.496C>T) is very rare (popmax 0.00217%, amr) (gnomAD).

How is Fabry disease inherited?

Typically X-linked dominant, X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

GLA p.Leu166=

c.496C>T · rs1928320069 · VCV2731356

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00217%, amr)

Conditions

Fabry disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.9	GERP 2.5, phastCons 1
Overall
CADD	11.96	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00217% Admixed American · 1/45,991 alleles

Overall 8.26e-05% 1/1,210,421 alleles · very rare exomes 1/1,097,023 · genomes 0/113,398 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GLA
Protein: p.Leu166=
Coding: c.496C>T
MANE Select: NM_000169
dbSNP: rs1928320069
Type: single nucleotide variant
Location: chrX:101401683 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 166: a UniProt-annotated variant site (in fabryd); a β-strand

Full GLA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Fabry disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Fabry disease (Orphanet):

Inheritance: X-linked dominant, X-linked recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

GLA p.Leu166Pro Likely pathogenic ★ same residue
GLA p.Leu166Val Pathogenic ★ ⚠ same residue
GLA p.Leu166Met Uncertain significance ★ ⚠ same residue
GLA p.Leu166Gly Conflicting classifications of pathogenicity ★ same residue
GLA c.1000-10G>A Likely pathogenic ★★ same condition
GLA c.1000-1G>A Pathogenic ★★ same condition
GLA c.1000-1G>C Pathogenic ★★ same condition
GLA c.1023A>C Pathogenic/Likely pathogenic ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/gla-p-leu166 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown