Is GLA p.Gln321= (c.963G>A) pathogenic?

GLA p.Gln321= (c.963G>A) is classified Likely benign in GLA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-10). Very rare (popmax 0.00438%, amr); Associated with Fabry disease.

What condition is associated with GLA p.Gln321= (c.963G>A)?

GLA p.Gln321= (c.963G>A) is associated with Fabry disease (ClinVar).

How common is GLA p.Gln321= (c.963G>A) in the general population?

GLA p.Gln321= (c.963G>A) is very rare (popmax 0.00438%, 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.Gln321=

c.963G>A · rs1001403373 · VCV1171619

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00438%, amr)

Conditions

Fabry disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.43	GERP 1.2, phastCons 1
Overall
CADD	3.244	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00438% Admixed American · 2/45,626 alleles

Filtering AF 0.000727% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000272%

Overall 0.000414% 5/1,207,869 alleles · very rare exomes 3/1,096,726 · genomes 2/111,143 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00438%	22,813
European (non-Finnish)	0.000336%	297,940

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.Gln321=
Coding: c.963G>A
MANE Select: NM_000169
dbSNP: rs1001403373
Type: single nucleotide variant
Location: chrX:101398406 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 321: a UniProt-annotated variant site (in fabryd)

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.Gln321Arg Pathogenic/Likely pathogenic ★★ ⚠ same residue
GLA p.Gln321Glu Likely pathogenic ★★ ⚠ same residue
GLA p.Gln321His Likely pathogenic ★ same residue
GLA p.Gln321Leu Likely pathogenic ★ same residue
GLA p.Gln321Ter Pathogenic ★ same residue
GLA p.Gln321Lys Uncertain significance ★ ⚠ same residue
GLA p.Gln321_Asp322delinsHisAsn Likely pathogenic ★ same residue
GLA c.1000-10G>A 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-gln321 (accessed [today's date]).

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