Is GLA p.Leu45Val (c.133C>G) pathogenic?

GLA p.Leu45Val (c.133C>G) is classified Uncertain significance in GLA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-16). AlphaMissense: likely benign (0.257); Absent from gnomAD v4.1; Associated with Fabry disease.

What condition is associated with GLA p.Leu45Val (c.133C>G)?

GLA p.Leu45Val (c.133C>G) is associated with Fabry disease (ClinVar).

How common is GLA p.Leu45Val (c.133C>G) in the general population?

GLA p.Leu45Val (c.133C>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.Leu45Val (c.133C>G)?

AlphaMissense predicts likely benign (score 0.257) — an in-silico prediction, not a clinical call.

GLA p.Leu45Val

c.133C>G · rs143084761 · VCV2870511

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.257 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fabry disease

Computational evidence

Protein change
AlphaMissense	0.257	likely benign
REVEL	0.712	pathogenic-leaning
SaProt	LLR -9.80	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.53, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 3,899 bp · p 4.8e-07 · regional, not allelic
Overall
CADD	24.9	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.Leu45Val
Coding: c.133C>G
MANE Select: NM_000169
dbSNP: rs143084761
Type: single nucleotide variant
Location: chrX:101407771 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 45: a β-strand; a UniProt-annotated variant site (in fabryd); a UniProt-annotated variant site (in fabryd; loss of enzyme activity)

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.Leu45= Likely benign ★★ same residue
GLA p.Leu45Arg Likely pathogenic ★ same residue
GLA p.Leu45Pro Pathogenic ★ same residue
GLA p.Leu45_His46delinsArgSer 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
GLA c.1023A>C Pathogenic/Likely 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-leu45val (accessed [today's date]).

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