Is GLA p.Val376= (c.1128G>A) pathogenic?

GLA p.Val376= (c.1128G>A) is classified Likely benign in GLA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). Very rare (popmax 0.000112%, nfe); Associated with Fabry disease.

What condition is associated with GLA p.Val376= (c.1128G>A)?

GLA p.Val376= (c.1128G>A) is associated with Fabry disease (ClinVar).

How common is GLA p.Val376= (c.1128G>A) in the general population?

GLA p.Val376= (c.1128G>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.

GLA p.Val376=

c.1128G>A · VCV3654021

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Conditions

Fabry disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.59	GERP -2.3, phastCons 0.017
Overall
CADD	6.476	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000112% European (non-Finnish) · 1/894,879 alleles

Overall 9.11e-05% 1/1,097,496 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.Val376=
Coding: c.1128G>A
MANE Select: NM_000169
Type: single nucleotide variant
Location: chrX:101397971 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 376: a turn

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.Val376Glu Uncertain significance ★★ ⚠ same residue
GLA p.Val376fs Pathogenic/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
GLA c.194+1G>A Pathogenic ★★ same condition
GLA c.194+1G>T 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-val376 (accessed [today's date]).

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