Is GLA p.Arg342Gln (c.1025G>A) pathogenic?

GLA p.Arg342Gln (c.1025G>A) is classified Pathogenic in GLA (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-09-08). AlphaMissense: ambiguous (0.4255); Very rare (popmax 0.000112%, nfe); Associated with Fabry disease.

What condition is associated with GLA p.Arg342Gln (c.1025G>A)?

GLA p.Arg342Gln (c.1025G>A) is associated with Fabry disease (ClinVar).

How common is GLA p.Arg342Gln (c.1025G>A) in the general population?

GLA p.Arg342Gln (c.1025G>A) is very rare (popmax 0.000112%, nfe) (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.Arg342Gln (c.1025G>A)?

AlphaMissense predicts ambiguous (score 0.4255) — an in-silico prediction, not a clinical call.

GLA p.Arg342Gln

c.1025G>A · rs28935493 · VCV10742

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

ambiguous

0.4255 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Fabry disease

Computational evidence

Protein change
AlphaMissense	0.4255	ambiguous
REVEL	0.904	moderately pathogenic-leaning
SaProt	LLR -12.51	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	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	26.0	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

Grpmax group 0.000112% European (non-Finnish) · 1/894,994 alleles

Overall 0.00089% 1/112,349 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.Arg342Gln
Coding: c.1025G>A
MANE Select: NM_000169
dbSNP: rs28935493
Type: single nucleotide variant
Location: chrX:101398074 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 342: a UniProt-annotated variant site (in fabryd; loss of enzyme activity); 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.Arg342Ter Pathogenic ★★ same residue
GLA p.Arg342Leu Pathogenic ★ same residue
GLA p.Arg342Pro Likely pathogenic ★ same residue
GLA p.Arg342fs Pathogenic ★ same residue
GLA p.Arg342Gly Likely pathogenic ★ 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

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-arg342gln (accessed [today's date]).

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