Is GLA p.Lys426fs (c.1277_1278del) pathogenic?

GLA p.Lys426fs (c.12771278del) is classified Conflicting classifications of pathogenicity in GLA (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-09-08). Very rare (popmax 0.000113%, nfe); Associated with Fabry disease.

What condition is associated with GLA p.Lys426fs (c.1277_1278del)?

GLA p.Lys426fs (c.1277_1278del) is associated with Fabry disease (ClinVar).

How common is GLA p.Lys426fs (c.1277_1278del) in the general population?

GLA p.Lys426fs (c.1277_1278del) is very rare (popmax 0.000113%, 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.Lys426fs

c.1277_1278del · rs869312249 · VCV10772

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000113%, nfe)

Conditions

Fabry disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon in the last exon (7 of 7) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.9	GERP -2.9

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000113% European (non-Finnish) · 1/884,884 alleles

Overall 8.33e-05% 1/1,200,308 alleles · very rare exomes 1/1,086,437 · genomes 0/113,871 · 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.Lys426fs
Coding: c.1277_1278del
MANE Select: NM_000169
dbSNP: rs869312249
Type: Deletion
Location: chrX:101397821 (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 c.548del Pathogenic ★★ same condition
GLA c.802-3_802-2del Pathogenic ★★ same condition
GLA c.803_806del Pathogenic ★★ same condition
GLA p.Ala190fs Pathogenic ★★ same condition
GLA p.Ala288fs Pathogenic/Likely pathogenic ★★ same condition
GLA p.Ala352fs Pathogenic ★★ same condition
GLA p.Asn355_Ile359del Likely pathogenic ★★ same condition
GLA p.Cys174fs 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-lys426fs (accessed [today's date]).

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