Is GLA p.Pro40Arg (c.119C>G) pathogenic?

GLA p.Pro40Arg (c.119C>G) is classified Conflicting classifications of pathogenicity in GLA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-09-08). AlphaMissense: likely pathogenic (0.8863); Absent from gnomAD v4.1; Associated with Fabry disease.

What condition is associated with GLA p.Pro40Arg (c.119C>G)?

GLA p.Pro40Arg (c.119C>G) is associated with Fabry disease (ClinVar).

How common is GLA p.Pro40Arg (c.119C>G) in the general population?

GLA p.Pro40Arg (c.119C>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.Pro40Arg (c.119C>G)?

AlphaMissense predicts likely pathogenic (score 0.8863) — an in-silico prediction, not a clinical call.

GLA p.Pro40Arg

c.119C>G · rs398123199 · VCV92539

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8863 · 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	0.8863	likely pathogenic
REVEL	0.966	strongly pathogenic-leaning
SaProt	LLR -14.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 3.4, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 123 bp · p 0.7 · 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.Pro40Arg
Coding: c.119C>G
dbSNP: rs398123199
Type: single nucleotide variant
Location: chrX:101407785 (GRCh38)

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)

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-pro40arg (accessed [today's date]).

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