Is GLA p.Ala352Ser (c.1054G>T) pathogenic?

GLA p.Ala352Ser (c.1054G>T) is classified Uncertain significance in GLA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-22). AlphaMissense: likely benign (0.2339); Absent from gnomAD v4.1; Associated with Fabry disease.

What condition is associated with GLA p.Ala352Ser (c.1054G>T)?

GLA p.Ala352Ser (c.1054G>T) is associated with Fabry disease (ClinVar).

How common is GLA p.Ala352Ser (c.1054G>T) in the general population?

GLA p.Ala352Ser (c.1054G>T) is absent from gnomAD v4.1 (gnomAD).

How is Fabry disease inherited?

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

What do computational predictors say about GLA p.Ala352Ser (c.1054G>T)?

AlphaMissense predicts likely benign (score 0.2339) — an in-silico prediction, not a clinical call.

GLA p.Ala352Ser

c.1054G>T · VCV3699294

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2339 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fabry disease

Computational evidence

Protein change
AlphaMissense	0.2339	likely benign
REVEL	0.685	pathogenic-leaning
SaProt	LLR -10.34	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 3.1, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 6,067 bp · p 6.6e-08 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GLA
Protein: p.Ala352Ser
Coding: c.1054G>T
MANE Select: NM_000169
Type: single nucleotide variant
Location: chrX:101398045 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 352: a UniProt-annotated variant site (in fabryd; uncertain significance; decreased enzyme activity); 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.Ala352Asp Pathogenic ★ same residue
GLA p.Ala352Pro Likely pathogenic ★ same residue
GLA p.Ala352Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
GLA p.Ala352Val Uncertain significance ★ ⚠ same residue
GLA p.Ala352fs Pathogenic ★★ same residue
GLA p.Ala352_Met353insThr Likely pathogenic ★ same residue
GLA c.1000-10G>A Likely pathogenic ★★ same condition
GLA c.1000-1G>A 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-ala352ser (accessed [today's date]).

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