Is GLA p.Gln2Pro (c.5A>C) pathogenic?

GLA p.Gln2Pro (c.5A>C) is classified Uncertain significance in GLA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-30). AlphaMissense: likely benign (0.0571); Very rare (popmax 0.000112%, nfe); Associated with Fabry disease.

What condition is associated with GLA p.Gln2Pro (c.5A>C)?

GLA p.Gln2Pro (c.5A>C) is associated with Fabry disease (ClinVar).

How common is GLA p.Gln2Pro (c.5A>C) in the general population?

GLA p.Gln2Pro (c.5A>C) 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.Gln2Pro (c.5A>C)?

AlphaMissense predicts likely benign (score 0.0571) — an in-silico prediction, not a clinical call.

GLA p.Gln2Pro

c.5A>C · VCV3673572

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0571 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fabry disease

Computational evidence

Protein change
AlphaMissense	0.0571	likely benign
REVEL	0.177	moderately benign-leaning
SaProt	LLR -5.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.5	GERP -2.6
Regional constraint	o/e 0.93	unconstrained · MANE · 123 bp · p 0.7 · regional, not allelic
Overall
CADD	5.35	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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) · 1/893,074 alleles

Overall 8.28e-05% 1/1,207,703 alleles · very rare exomes 0/1,095,529 · genomes 1/112,174 · 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.Gln2Pro
Coding: c.5A>C
MANE Select: NM_000169
Type: single nucleotide variant
Location: chrX:101407899 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB

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.Gln2Ter Pathogenic ★★ same residue
GLA p.Gln2Arg Uncertain significance ★★ ⚠ same residue
GLA p.Gln2= Likely benign ★★ same residue
GLA p.Gln2His Uncertain significance ★ ⚠ same residue
GLA p.Gln2_Leu3insTer Pathogenic ★ same residue
GLA p.Gln2Leu Likely benign ★ 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-gln2pro (accessed [today's date]).

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