Is GLA p.Asn228= (c.684T>C) pathogenic?

GLA p.Asn228= (c.684T>C) is classified Likely benign in GLA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-30). Very rare (popmax 0.00176%, sas); Associated with Fabry disease.

What condition is associated with GLA p.Asn228= (c.684T>C)?

GLA p.Asn228= (c.684T>C) is associated with Fabry disease (ClinVar).

How common is GLA p.Asn228= (c.684T>C) in the general population?

GLA p.Asn228= (c.684T>C) is very rare (popmax 0.00176%, sas) (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.Asn228=

c.684T>C · VCV4757362

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00176%, sas)

Conditions

Fabry disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4.6	GERP 3.2, phastCons 1
Overall
CADD	7.711	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00176% South Asian · 1/56,892 alleles

Overall 9.13e-05% 1/1,094,719 alleles · very rare

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.Asn228=
Coding: c.684T>C
Type: single nucleotide variant
Location: chrX:101398902 (GRCh38)

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)

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-asn228 (accessed [today's date]).

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