Is GLA p.Arg118His (c.353G>A) pathogenic?

GLA p.Arg118His (c.353G>A) is classified Conflicting classifications of pathogenicity in GLA (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-09-08). AlphaMissense: likely benign (0.0651); Very rare (popmax 0.00697%, afr); Associated with Fabry disease.

What condition is associated with GLA p.Arg118His (c.353G>A)?

GLA p.Arg118His (c.353G>A) is associated with Fabry disease (ClinVar).

How common is GLA p.Arg118His (c.353G>A) in the general population?

GLA p.Arg118His (c.353G>A) is very rare (popmax 0.00697%, afr) (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.Arg118His (c.353G>A)?

AlphaMissense predicts likely benign (score 0.0651) — an in-silico prediction, not a clinical call.

GLA p.Arg118His

c.353G>A · rs143768851 · VCV222219

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0651 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00697%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fabry disease

Computational evidence

Protein change
AlphaMissense	0.0651	likely benign
REVEL	0.282	benign-leaning
SaProt	LLR -8.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.7	GERP -2.5
Regional constraint	o/e 0.66	unconstrained · MANE · 6,067 bp · p 6.6e-08 · regional, not allelic
Overall
CADD	5.502	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

Grpmax group 0.00697% African / African-American · 4/57,357 alleles

Filtering AF 0.00233% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0014%

Overall 0.00157% 19/1,209,227 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00697%	14,339
Ashkenazi Jewishnot grpmax-eligible	0.00454%	22,029
European (non-Finnish)	0.00157%	63,857

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.Arg118His
Coding: c.353G>A
MANE Select: NM_000169
dbSNP: rs143768851
Type: single nucleotide variant
Location: chrX:101403827 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 118: an α-helix

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.Arg118Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
GLA p.Arg118Gly Uncertain significance ★ ⚠ same residue
GLA p.Arg118Ser Uncertain significance ★ ⚠ 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

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-arg118his (accessed [today's date]).

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