Is GLA p.Cys52Trp (c.156C>G) pathogenic?

GLA p.Cys52Trp (c.156C>G) is classified Conflicting classifications of pathogenicity in GLA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-09-08). AlphaMissense: likely pathogenic (0.9284); Absent from gnomAD v4.1; Associated with Fabry disease.

What condition is associated with GLA p.Cys52Trp (c.156C>G)?

GLA p.Cys52Trp (c.156C>G) is associated with Fabry disease (ClinVar).

How common is GLA p.Cys52Trp (c.156C>G) in the general population?

GLA p.Cys52Trp (c.156C>G) 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.Cys52Trp (c.156C>G)?

AlphaMissense predicts likely pathogenic (score 0.9284) — an in-silico prediction, not a clinical call.

GLA p.Cys52Trp

c.156C>G · VCV4087282

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9284 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fabry disease

Computational evidence

Protein change
AlphaMissense	0.9284	likely pathogenic · top 7% in GLA
REVEL	0.881	moderately pathogenic-leaning
SaProt	LLR -15.17	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 3,899 bp · p 4.8e-07 · regional, not allelic
Overall
CADD	25.0	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

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.Cys52Trp
Coding: c.156C>G
MANE Select: NM_000169
Type: single nucleotide variant
Location: chrX:101407748 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 52: a UniProt-annotated variant site (in fabryd); a disulfide bond

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.Cys52Arg Pathogenic ★★ same residue
GLA p.Cys52Gly Pathogenic/Likely pathogenic ★★ same residue
GLA p.Cys52Ser Pathogenic ★★ same residue
GLA p.Cys52Tyr Pathogenic ★★ same residue
GLA p.Cys52Phe Likely pathogenic ★ same residue
GLA p.Cys52Ter Pathogenic ★ same residue
GLA p.Cys52= Likely benign ★ same residue
GLA p.Cys52fs Pathogenic/Likely pathogenic ★★ same residue

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-cys52trp (accessed [today's date]).

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