Is GLA p.Arg227Ter (c.679C>T) pathogenic?

GLA p.Arg227Ter (c.679C>T) is classified Pathogenic in GLA (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-09-08). Very rare (popmax 0.00176%, sas); Associated with GLA-related disorder.

What condition is associated with GLA p.Arg227Ter (c.679C>T)?

GLA p.Arg227Ter (c.679C>T) is associated with GLA-related disorder, Fabry disease (ClinVar).

How common is GLA p.Arg227Ter (c.679C>T) in the general population?

GLA p.Arg227Ter (c.679C>T) is very rare (popmax 0.00176%, sas) (gnomAD).

GLA p.Arg227Ter

c.679C>T · rs104894841 · VCV10733

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00176%, sas)

Conditions

GLA-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 5 of 7
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.39	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 4.3	GERP 2, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00176% South Asian · 1/56,692 alleles

Overall 0.000166% 2/1,205,421 alleles · very rare exomes 1/1,093,443 · genomes 1/111,978 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00176%	56,692
European (non-Finnish)	0.000112%	891,266

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.Arg227Ter
Coding: c.679C>T
MANE Select: NM_000169
dbSNP: rs104894841
Type: single nucleotide variant
Location: chrX:101398907 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 227: a UniProt-annotated variant site (in fabryd; loss of enzyme activity); a UniProt-annotated variant site (in fabryd); a β-strand

Full GLA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

GLA-related disorder

Also linked: Fabry disease

Similar variants

GLA p.Arg227Gln Pathogenic ★★ same residue
GLA p.Arg227= Likely benign ★★ same residue
GLA p.Arg227Gly Likely pathogenic ★ same residue
GLA p.Arg227Leu Likely pathogenic ★ same residue
GLA p.Arg227Pro 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

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-arg227ter (accessed [today's date]).

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